Benzoxazole carboxamides for treating CINV and IBS-D

ABSTRACT

Compounds of formulae I and II:  
                 
 
are disclosed as 5-HT 3  inhibitors. Those compounds that exhibit central activity are useful in treating CINV; those that inhibit peripheral receptors are useful to treat IBS-D.

CROSS-REFERENCE TO RELATED APPLICATIONS

This application claims the priority of U.S. provisional application60/653,821, filed Feb. 17, 2005.

STATEMENT REGARDING FEDERALLY SPONSORED RESEARCH OR DEVELOPMENT

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NAMES OF PARTIES TO A JOINT RESEARCH AGREEMENT

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REFERENCE TO SEQUENCE LISTING

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BACKGROUND OF THE INVENTION

1. Field of the Invention

The invention relates to a genus of benzoxazole carboxamides that areuseful in treating chemotherapy-induced nausea and vomiting (CINV) andin treating diarrhea-predominant Irritable Bowel Syndrome (IBS-D).

2. Background

Nausea and vomiting caused by chemotherapy remain among the mostdistressing side effects for patients undergoing treatment for cancer.Depending upon the chemotherapy agents or regimens given, up to 90% ofpatients may suffer from some form of chemotherapy-induced nausea andvomiting (CINV). Symptoms from CINV can be severely debilitating andoften result in patients refusing further courses of chemotherapy, withobviously unfavorable consequences as regards progression of the cancer.Furthermore, CINV is burdensome on the medical system, consuming timefrom the healthcare staff, who could otherwise attend to other patientsor medical issues.

CINV is divided into two main categories: acute CINV and delayed CINV.Acute CINV occurs within the first 24 hours of treatment; delayed CINVoccurs from 24 hours to 120 hours following treatment. Delayed CINVremains a highly under treated side effect in patients undergoingchemotherapy, as healthcare providers tend to underestimate the numberof patients who suffer from delayed CINV. Furthermore, delayed CINVgreatly impairs patients' ability to provide care to themselves oncethey have been discharged.

Compounds that inhibit central receptors are currently the mosteffective anti-emetics; they constitute the single greatest advance inthe management of nausea and vomiting in patients with cancer. Blockingthe 5-HT₃ signal in the CNS appears to prevent acute emesis. Allapproved 5-HT₃ inhibitors, except palonosetron (ALOXI™), are approved toprevent acute CINV. Palonosetron, which must be given intravenously, isthe only 5-HT₃ inhibitor currently approved for the prevention ofdelayed CINV. This appears to be due to its long serum half-life.Therefore persons of skill in the art accept that 5-HT₃ inhibitors thathave long serum half-lives will be effective therapeutic agents for bothacute and delayed CINV; those that have short will be useful to treatacute CINV. In addition, the combination of palonosetron, a 5-HT₃inhibitor, and aprepitant (EMEND®), a neurokinin antagonist, has beenshown to be highly effective in preventing both acute and delayed CINVfollowing a variety of moderately to highly emetogenic chemotherapyregimens in clinical trials. A large number of other 5-HT₃ inhibitors ofthe “setron” class have been described in clinical and preclinical usefor CINV [see review article by Israili, Curr. Med. Chem. CNS Agents 1171-199 (2001), which is incorporated herein by reference].

Irritable Bowel Syndrome (IBS) generally occurs in two types: diarrheapredominant (IBS-D) and constipation predominant (IBS-C). Diarrheapredominant Irritable Bowel Syndrome is a debilitating, though seldomfatal, disease. The typical sufferer of IBS-D exhibits primary symptomsincluding multiple and daily explosive diarrhea attacks and severe dailyabdominal cramps. The most common secondary side effects include panicattacks, depression, withdrawal from social and family activities andmalnutrition.

At present, compounds that inhibit peripheral 5-HT₃ receptors are theonly effective treatment for IBS-D. The only drug currently approved forIBS-D is alosetron, which was introduced by Glaxo, withdrawn from theclinical trial by the FDA because it caused ischemic colitis, thenreinstated by the FDA because the demand was so great for some treatmentfor IBS-D. In 2002, the US Food and Drug Administration approvedalosetron hydrochloride (LOTRONEX®) tablets under restricted conditionsfor patients in whom the medical benefits outweigh the risks. Therestrictions on the approval reflect the serious gastrointestinaladverse events that have been reported with the use of alosetron. Asecond peripheral 5-HT₃ inhibitor, cilanestron, was in clinical trials.Clearly there is a need for improved therapy for both CINV and IBS-D.

SUMMARY OF THE INVENTION

It has now been found that compounds of formulae I and II are potent andselective inhibitors of the 5-HT₃ receptor:

In these compoundsR¹, R² and R³ are independently selected from hydrogen, halogen, amino,alkylamino, dialkylamino, acylamino, morpholinyl, —O-loweralkyl,hydroxy, loweralkyl, fluoroloweralkyl, —O-lowerfluoroalkyl,methylenedioxy, ethylenedioxy, alkoxy-loweralkyl and hydroxyloweralkyl;R⁴ is a residue chosen from:(i) a saturated nitrogen heterocycle or methyl-substituted saturatednitrogen heterocycle, in which said nitrogen is tertiary, saidheterocycle containing at least one 5 or 6-membered ring; and(ii) an imidazolylalkyl residue wherein the imidazole of saidimidazolylalkyl is optionally substituted with up to three groups chosenfrom halogen, (C₁-C₄)alkyl, substituted (C₁-C₄)alkyl and NH₂; andAr is chosen from the group consisting of(i) aryl;(ii) heteroaryl;(iii) substituted aryl;(iv) substituted heteroaryl; and(v) dihydroheteroaryl.

Those members of the genus that are selective for central receptors areuseful to treat CINV; those members of the genus that are selective forperipheral receptors are useful to treat IBS-D.

In another aspect, the invention relates to pharmaceutical compositionscomprising a pharmaceutically acceptable carrier and a therapeuticallyeffective amount of a compound of formula I or II. The compositions maycomprise an additional antiemetic agent, particularly a neurokininantagonist.

In another aspect, the invention relates to a method of treating adisorder arising from inappropriate activity of the serotonin type 3receptor or dependent upon modulation of the serotonin type 3 receptor.The method comprises administering a therapeutically effective amount ofa compound of formula I or II. Exemplary disorders arising frominappropriate activity of the serotonin type 3 receptor or dependentupon modulation of the serotonin type 3 receptor include emesis,particularly CINV, and IBS-D. Other such disorders include psychologicaldisorders, obesity, substance abuse disorders, dementia associated witha neurodegenerative disease, cognition loss, pain, fibromyalgia syndromeand chronic fatigue syndrome (see US published application2004/0204467). Serotonin type 3 receptor antagonists are also known tobe useful for the prevention and treatment of bronchial asthma.

DETAILED DESCRIPTION OF THE INVENTION

Throughout this specification the substituents are defined whenintroduced and retain their definitions.

In a first aspect the invention relates to compounds of formula I and II

Two subgenera are:

In these subgeneric compounds,R¹, R² and R³ are independently selected from hydrogen, halogen, amino,alkylamino, dialkylamino, acylamino, morpholinyl, —O-loweralkyl,hydroxy, loweralkyl, fluoroloweralkyl, —O-lowerfluoroalkyl,methylenedioxy, ethylenedioxy, alkoxy-loweralkyl and hydroxyloweralkyl;

represents a saturated nitrogen heterocycle or methyl-substitutedsaturated nitrogen heterocycle. In the heterocycle, any ring nitrogen istertiary, and the heterocycle contains at least one 5 or 6-memberedring;

represents a saturated nitrogen heterocycle or methyl-substitutedsaturated nitrogen heterocycle. As before, the nitrogen is tertiary, butin structure II the heterocycle contains at least two 6-membered rings;Ar is chosen from the group consisting of(i) aryl;(ii) heteroaryl;(iii) aryl substituted with from one to four substitutents chosen fromlower alkoxy, phenoxy, trialkylsilylacetylenyl, anilino, lower alkynyl,lower alkyl, halogen, nitro, cyano, hydroxy, amino, methylenedioxy,alkylamino, dialkylamino, phenyl, heterocyclyl, methylheterocyclyl,methylenedioxy and acylamino;(iv) heteroaryl substituted with one or two substitutents chosen fromoxo, halogen, and alkyl; and(v) dihydroheteroaryl.

In two other subgenera, R⁴ is imidazolylalkyl:

in whichR⁷, R⁸ and R⁹ are independently selected from hydrogen, halogen, amino,alkylamino, dialkylamino, acylamino, loweralkyl, fluoroloweralkyl andhydroxyloweralkyl; andp is an integer from 1 to 4.

Compounds falling within the foregoing parent genus and its subgeneraare useful as 5-HT₃ inhibitors. It may be found upon examination thatcompounds that are not presently excluded from the claims are notpatentable to the inventors in this application. In that case, theexclusion of species and genera in applicants' claims are to beconsidered artifacts of patent prosecution and not reflective of theinventors' concept or description of their invention. The invention, ina composition aspect, is all compounds of formulae I, Ia, II and IIa,except those that are in the public's possession.

Definitions

Alkyl is intended to include linear, branched, or cyclic hydrocarbonstructures and combinations thereof. Lower alkyl refers to alkyl groupsof from 1 to 6 carbon atoms. Examples of lower alkyl groups includemethyl, ethyl, propyl, isopropyl, butyl, s- and t-butyl and the like.Preferred alkyl groups are those of C₂₀ or below. Cycloalkyl is a subsetof alkyl and includes cyclic hydrocarbon groups of from 3 to 8 carbonatoms. Examples of cycloalkyl groups include c-propyl, c-butyl,c-pentyl, norbornyl and the like.

C₁ to C₂₀ hydrocarbon includes alkyl, cycloalkyl, alkenyl, alkynyl, aryland combinations thereof. Examples include phenethyl, cyclohexylmethyl,camphoryl and naphthylethyl.

Alkoxy or alkoxyl refers to groups of from 1 to 8 carbon atoms of astraight, branched, cyclic configuration and combinations thereofattached to the parent structure through an oxygen. Examples includemethoxy, ethoxy, propoxy, isopropoxy, cyclopropyloxy, cyclohexyloxy andthe like. Lower-alkoxy refers to groups containing one to four carbons.

Oxaalkyl refers to alkyl residues in which one or more carbons has beenreplaced by oxygen. Examples include methoxypropoxy, 3,6,9-trioxadecyland the like.

Acyl refers to groups of from 1 to 8 carbon atoms of a straight,branched, cyclic configuration, saturated, unsaturated and aromatic andcombinations thereof, attached to the parent structure through acarbonyl functionality. One or more carbons in the acyl residue may bereplaced by nitrogen, oxygen or sulfur as long as the point ofattachment to the parent remains at the carbonyl. Examples includeacetyl, benzoyl, propionyl, isobutyryl, t-butoxycarbonyl,benzyloxycarbonyl and the like. Lower-acyl refers to groups containingone to four carbons.

Aryl and heteroaryl mean a 5- or 6-membered aromatic or heteroaromaticring containing 0-3 heteroatoms selected from O, N, or S; a bicyclic 9-or 10-membered aromatic or heteroaromatic ring system containing 0-3heteroatoms selected from O, N, or S; or a tricyclic 13- or 14-memberedaromatic or heteroaromatic ring system containing 0-3 heteroatomsselected from O, N, or S. The aromatic 6- to 14-membered carbocyclicrings include, e.g., benzene, naphthalene, indane, tetralin, andfluorene and the 5- to 10-membered aromatic heterocyclic rings include,e.g., imidazole, pyridine, indole, thiophene, benzopyranone, thiazole,furan, benzimidazole, quinoline, isoquinoline, quinoxaline, pyrimidine,pyrazine, tetrazole and pyrazole.

Arylalkyl refers to a residue in which an aryl moiety is attached to theparent through an alkyl. Examples are benzyl, phenethyl and the like.Tolyl is not arylalkyl; tolyl is alkylaryl. Heteroarylalkyl means aheteroaryl residue attached to the parent via alkyl. Examples include,e.g., pyridinylmethyl, pyrimidinylethyl and the like.

Heterocycle means a cycloalkyl or aryl residue in which from one tothree carbons is replaced by a heteroatom selected from the groupconsisting of N, O and S. The nitrogen and sulfur heteroatoms mayoptionally be oxidized, and the nitrogen heteroatom may optionally bequaternized. Examples of heterocycles include pyrrolidine, pyrazole,pyrrole, indole, quinoline, isoquinoline, tetrahydroisoquinoline,benzofuran, benzodioxan, benzodioxole (commonly referred to asmethylenedioxyphenyl, when occurring as a substituent), tetrazole,morpholine, thiazole, pyridine, pyridazine, pyrimidine, thiophene,furan, oxazole, oxazoline, isoxazole, dioxane, tetrahydrofuran and thelike. Nitrogen heterocycles are heterocycles containing at least onenitrogen. They may additionally include other heteroatoms and multiplenitrogens. Examples include quinuclidine, tropane, piperidine,piperazine, morpholine, quinoline and thiazole. It is to be noted thatheteroaryl is a subset of heterocycle in which the heterocycle isaromatic. Dihydroheteroaryl are, as the name implies, heteraryl residuesformally reduced by one mole of hydrogen. An examples of adihydroheteroaryl residue is 2,3-dihydrobenzofuran.

Substituted alkyl, aryl, cycloalkyl, heterocyclyl etc. refer to alkyl,aryl, cycloalkyl, or heterocyclyl wherein up to four H atoms in eachresidue are replaced with halogen, haloalkyl, hydroxy, loweralkoxy,carboxy, alkoxycarbonyl (COOR), carboxamido (—CONR₂), sulfonamido(—SO₂NR₂), cyano, carbonyl, nitro, amino, alkylamino, dialkylamino,mercapto, alkylthio, sulfoxide, sulfone, acylamino, amidino, phenyl,benzyl, heteroaryl, phenoxy, benzyloxy, or heteroaryloxy. In theforegoing listing, R is hydrogen or alkyl.

The term “halogen” means fluorine, chlorine, bromine or iodine.

Some of the compounds described herein may contain one or moreasymmetric centers and may thus give rise to enantiomers, diastereomers,and other stereoisomeric forms that may be defined, in terms of absolutestereochemistry, as (R)- or (S)-. The present invention is meant toinclude all such possible isomers, as well as, their racemic andoptically pure forms. Optically active (R)- and (S)-isomers may beprepared using chiral synthons or chiral reagents, or resolved usingconventional techniques. When the compounds described herein containolefinic double bonds or other centers of geometric asymmetry, andunless specified otherwise, it is intended that the compounds includeboth E and Z geometric isomers. Likewise, all tautomeric forms are alsointended to be included. The configuration of any carbon-carbon doublebond appearing herein is selected for convenience only and is notintended to designate a particular configuration; thus a carbon-carbondouble bond depicted arbitrarily herein as trans may be Z, E or amixture of the two in any proportion.

It will be recognized that the compounds of this invention can exist inradiolabeled form, i.e., the compounds may contain one or more atomscontaining an atomic mass or mass number different from the atomic massor mass number usually found in nature. Radioisotopes of hydrogen,carbon, phosphorous, fluorine, chlorine and iodine include ³H, ¹⁴C, ³⁵S,¹⁸F, ³⁶Cl and ¹²⁵I, respectively. Compounds that contain thoseradioisotopes and/or other radioisotopes of other atoms are within thescope of this invention. Tritiated, i.e. ³H, and carbon-14, i.e., ¹⁴C,radioisotopes are particularly preferred for their ease in preparationand detectability. Radiolabeled compounds of this invention cangenerally be prepared by methods well known to those skilled in the art.Conveniently, such radiolabeled compounds can be prepared by carryingout the procedures disclosed in the Examples and Schemes by substitutinga readily available radiolabeled reagent for a non-radiolabeled reagent.

The compounds of the invention may be conveniently divided into twosubgenera, the benzoxazole-4-carboxamides I and thebenzoxazole-7-carboxamides II:

In these compounds,

and represent saturated nitrogen heterocycles or methyl-substitutedsaturated nitrogen heterocycles, in which the nitrogen is tertiary. Incompounds of formula I, the heterocycle contains at least one 5 or6-membered ring; in compounds of formula II the heterocycle contains two6-membered rings. A nitrogen heterocycle (also referred to as anitrogenous heterocycle) is a heterocycle containing at least onenitrogen in the ring; it may contain additional nitrogens, as well asother heteroatoms. In one embodiment,

or

is chosen from:

wherein m=1, 2, 3 or 4; n=0, 1, 2, 3 or 4; and R⁵ is hydrogen or methyl.Nitrogenous heterocycles that appear in the examples include piperidine,methylpiperidine, quinuclidine, tropane, azabicyclo[3.3.1]nonane, methylazabicyclo[3.3.1]nonane and 9-azabicyclo[3.3.1]nonan-3-one. Othernitrogenous heterocycles include:

in which X is NCH₃, O, S, SO or SO₂.

In some embodiments R¹, R² and R³ are hydrogen. In other embodiments oneof R¹, R² and R³ is halogen. In other embodiments, R¹ and R³ arehydrogen and R² is chosen from amino, halogen, methoxy, hydroxy,acetylamino, and 4-morpholinyl.

In some embodiments Ar is chosen from the group consisting of phenyl andphenyl substituted with from 1 to 4 groups independently selected from(C₁ to C₄)alkyl, phenyl, phenoxy, halogen, (C₁ to C₄)alkoxy, amino, (C₁to C₄)alkylamino, di(C₁ to C₄)alkylamino [e.g. dimethylamino], anilino,heterocyclyl [e.g. morpholin-4-yl and pyridin-4-yl], methylheterocyclyl[e.g. 4-methylpiperazinl-yl], methylenedioxy, (C₁ to C₄)acylamino [e.g.acetylamino], (C₁ to C₄)alkynyl [e.g. propyn-1-yl] and nitro.

In other embodiments, Ar is chosen from the group consisting ofheteroaryl, dihydroheteroaryl and substituted heteroaryl. Examplesinclude compounds in which Ar is chosen from thiophene,cyclopenta[b]thiophene, furan, thiazole, isoxazole dihydrobenzofuran,benzofuran, pyridine benzothiophene, 3-pyridine-2-one, and theirmethylated and halogenated congeners. The term “methylated andhalogenated congeners” refers to heteroaryl and dihydroheteroarylsubstituted with from one to three methyls and/or halogens, for example,3,5-dimethylisoxazol-4-yl; 4-methylthiazol-5-yl and3-chlorothiophen-2-yl.

Terminology related to “protecting”, “deprotecting” and “protected”functionalities occurs throughout this application. Such terminology iswell understood by persons of skill in the art and is used in thecontext of processes which involve sequential treatment with a series ofreagents. In that context, a protecting group refers to a group which isused to mask a functionality during a process step in which it wouldotherwise react, but in which reaction is undesirable. The protectinggroup prevents reaction at that step, but may be subsequently removed toexpose the original functionality. The removal or “deprotection” occursafter the completion of the reaction or reactions in which thefunctionality would interfere. Thus, when a sequence of reagents isspecified, as it is in the processes of the invention, the person ofordinary skill can readily envision those groups that would be suitableas “protecting groups”. Suitable groups for that purpose are discussedin standard textbooks in the field of chemistry, such as ProtectiveGroups in Organic Synthesis by T. W. Greene [John Wiley & Sons, NewYork, 1991], which is incorporated herein by reference.

A comprehensive list of abbreviations utilized by organic chemistsappears in the first issue of each volume of the Journal of OrganicChemistry. The list, which is typically presented in a table entitled“Standard List of Abbreviations” is incorporated herein by reference.

Generalized synthetic schemes are presented below:

EXAMPLES

Exemplary syntheses are provided below.

Example 1 Preparation ofN-[3-(2-Methylimidazol-1-yl)propyl]-2-phenylbenzoxazole-4-carboxamide

Step A: To a suspension of 3-hydroxyanthranilic acid (0.300 g, 1.96mmol) in toluene (10 mL) was added benzoyl chloride (0.830 g, 5.90 mmol)followed by pyridine (0.545 g, 6.92 mmol) at room temperature. Theresulting mixture was stirred at room temperature for 30 min then heatedto 80° C. for 1 hr. After this time the reaction was cooled and pouredinto a mixture of ethyl acetate (50 mL) and 5% aqueous hydrochloric acid(50 mL). Subsequent separation of the layers, drying the organic overMgSO₄ and filtration afforded an orange solution. This solution wasconcentrated to an orange solid which was directly re-dissolved inxylenes (20 mL) and the solution treated with p-toluenesulfonic acid(0.800 g, 4.20 mmol). The reaction mixture was then heated to reflux for6 hrs. After this time the reaction was cooled and poured into water (50mL), the organic layer separated then washed with water (3×50 mL). Theorganic was dried over MgSO₄, filtered and concentrated to anorange/brown solid. Re-crystallization of this solid from ethyl acetateafforded 0.412 g (88% yield) of 2-phenylbenzoxazole-4-carboxylic acid asa light yellow solid: ¹H NMR (300 MHz, CD₃OD) δ 11.58 (br s, 1H), 8.30(m, 2H), 8.17 (dd, J=7.8, 0.8 Hz, 1H), 7.83 (dd, J=8.2, 0.8 Hz, 1H),7.69-7.45 (m, 4H); MS (APCI) m/z 240 [M+H]⁺.

Step B: A solution of 2-methylimidazole (0.820 g, 10.0 mmol) in DMF (10mL) was cooled in an ice/water bath and sodium hydroxide (1.00 g, 25.0mmol) added. The resulting mixture was stirred for 30 min, then2-chloropropylamine hydrochloride (1.30 g, 10.0 mmol) added in oneportion. The resulting suspension was then stirred for 16 h during whichtime the reaction slowly warmed to room temperature. After this time themixture was poured into water (500 mL) and the mixture extracted withether (3×100 mL). The combined ether extracts were dried over sodiumbicarbonate, filtered and concentrated under reduced pressure to afford0.726 g (52% yield) of 3-(2-methylimidazol-1-yl)propylamine as a yellowoil. ¹H NMR (300 MHz, CD₃OD) δ 7.00 (d, J=1.4 Hz, 1H), 6.79 (d, J=1.4Hz, 1H), 3.97 (t, J=7.3 Hz, 2H), 2.63 (t, J=7.1 Hz, 2H), 2.35 (s, 3H),1.87 (m, 2H).

Step C: A 100-mL one-neck round-bottomed flask equipped with a magneticstirrer was purged with nitrogen and charged with2-phenylbenzoxazole-4-carboxylic acid (0.190 g, 0.79 mmol), DMF (0.588g, 8.00 mmol) and anhydrous methylene chloride (15 mL). The resultingsolution was treated with oxalyl chloride (1.46 g, 11.5 mmol) dropwiseover 5 min and stirred at ambient temperature under nitrogen for 2 h.After this time, the reaction mixture was evaporated to a solid residuewhich was dissolved in anhydrous methylene chloride (15 mL). Theresulting solution was treated with sodium bicarbonate (0.672 g, 8.00mmol) and stirred at ambient temperature under nitrogen for 15 min.After this time, a solution of 3-(2-methylimidazol-1-yl)propylamine(0.332 g, 2.39 mmol) in anhydrous methylene chloride (5 mL) was addedand the mixture stirred for a further 20 h. The reaction mixture wasthen diluted with methylene chloride (50 mL) and washed with 10% aqueouspotassium carbonate (10 mL) followed by water (20 mL). The organic phasewas dried over sodium sulfate, filtered and evaporated to a solidresidue which was further purified by preparative HPLC to give 0.040 g(14% yield) ofN-[3-(2-methylimidazol-1-yl)propyl]-2-phenylbenzoxazole-4-carboxamide asa white solid: mp 145-148° C.; ¹H NMR (300 MHz, CD₃OD) δ 8.33 (m, 2H),8.03 (dd, J=7.8, 0.9 Hz, 1H), 7.86 (dd, J=8.2, 0.9 Hz, 1H), 7.69-7.59(m, 4H), 7.52 (t, J=8.0 Hz, 1H), 7.38 (d, J=2.1 Hz, 1H), 4.32 (t, J=7.1Hz, 2H), 3.67 (t, J=7.1 Hz, 2H), 2.65 (s, 3H), 2.31 (m, 2H); MS (ESI)m/z 361 [M+H]⁺.

Example 2 Preparation ofN-[2-(2-Methylimidazol-1-yl)ethyl]-2-phenylbenzoxazole-4-carboxamide

Step A: 2-(2-Methylimidazol-1-yl)ethylamine was prepared from2-methylimidazole and 2-chloroethylamine hydrochloride using the methoddescribed in Step B of Example 1. This material was obtained as a lightyellow oil in 47% yield. ¹H NMR (300 MHz, CD₃OD) δ 6.95 (br s, 1H), 6.82(br s, 1H), 4.90 (bs, 2H), 3.90 (t, J=6.9 Hz, 2H), 2.93 (t, J=6.9 Hz,2H), 2.35 (s, 3H); MS (APCI) m/z 126 [M+H]⁺.

Step B:N-[2-(2-Methylimidazol-1-yl)ethyl]-2-phenylbenzoxazole-4-carboxamide wasprepared from 2-(2-methylimidazol-1-yl)ethylamine and2-phenylbenzoxazole-4-carboxylic acid using the conditions described inStep C of Example 1. This compound was obtained in 35% yield as a whitesolid; mp 125-127° C.; ¹H NMR (300 MHz, CD₃OD) δ 8.11 (dd, J=7.8, 1.0Hz, 2H), 7.96 (d, J=7.8 Hz, 1H), 7.73 (d, J=8.2 Hz, 1H), 7.63-7.52 (m,3H), 7.42 (t, J=8.0 Hz, 1H), 7.13 (s, 1H), 6.86 (s, 1H), 4.22 (t, J=5.8Hz, 2H), 3.87 (t, J=6.0 Hz, 2H), 2.34 (s, 3H); MS (APCI) m/z 347 [M+H]⁺

Example 4 Preparation ofN-(1-Methylpiperidin-4-yl)-2-phenylbenzoxazole-4-carboxamide

Step A: To a solution of 1-methyl-4-piperidone (1.84 g, 16.2 mmol) inMeOH (40 mL) was added a slurry of ammonium formate (10.2 g, 162 mmoL)in water (4.4 mL) and the reaction stirred until all of the solids haddissolved. Palladium on carbon, (3.78 g, 10% Pd, 50% wet) was then addedand the reaction stirred for 18 h at room temperature. After this timethe mixture was filtered through a pad of celite and the filtrateconcentrated under reduced pressure. The resulting viscous clear oil wasdissolved in EtOH (33 mL) and the solution treated with 37% hydrochloricacid (4.1 mL). After stirring at room temperature for 1 h, the solutionwas concentrated to a white solid which was re-crystallized from EtOH toafford 0.62 g (25% yield) of 4-amino-1-methylpiperidine dihydrochlorideas a white solid: ¹H NMR (300 MHz, DMSO-d₆) δ 10.95 (br s, 1H), 8.53 (brs, 3H), 3.42 (t, J=6.9 Hz, 3H), 3.23 (br s, 1H), 3.03 (t, J=11.7 Hz,1H), 2.67 (s, 3H), 2.12 (m, 2H), 1.97 (m, 2H).

Step B: N-(1-Methylpiperidin-4-yl)-2-phenylbenzoxazole-4-carboxamide wasprepared from 2-phenylbenzoxazole-4-carboxylic acid and4-amino-1-methylpiperidine dihydrochloride using the conditionsdescribed for Step C in Example 1. This compound was obtained in 38%yield as a white solid; mp 126-128° C.; ¹H NMR (300 MHz, CDCl₃) δ 9.26(d, J=7.5 Hz, 1H), 8.25 (m, 2H), 8.19 (d, J=7.7 Hz, 1H), 7.70 (d, J=8.1Hz, 1H), 7.63-7.53 (m, 3H), 7.46 (t, J=8.0 Hz, 1H), 4.20 (m, 1H), 2.86(m, 2H), 2.37 (s, 3H), 2.33-2.13 (m, 4H), 1.85-1.73 (m, 2H); MS (APCI)m/z 336 [M+H]⁺.

Example 5 Preparation ofN-(9-Methyl-9-azabicyclo[3.3.1]non-3-yl)-2-phenylbenzoxazole-4-carboxamide

Step A: A mixture of 9-methyl-9-aza-bicyclo[3.3.1]nonan-3-one (0.658 g,4.29 mmol) and hydroxylamine hydrochloride (0.312 g, 4.49 mmol) inmethanol (6 mL) was stirred for 20 h at room temperature, during whichtime a white precipitate formed. This solid was collected by filtration,rinsed with additional methanol (2×10 mL), and dried under vacuum for 1h to afford 0.672 g (76% yield) of9-methyl-9-aza-bicyclo[3.3.1]nonan-3-one oxime hydrochloride as a whitesolid: ¹H NMR (300 MHz, DMSO-d₆) d 10.82 (s, 1H), 3.71-3.52 (m, 2H),3.34-3.23 (m, 1H), 3.12 (d, J=17.5 Hz, 1H), 2.90-2.79 (m, 3H), 2.73-2.55(m, 1H), 2.42 (d, J=16.8 Hz, 1H), 2.27-2.05 (m, 2H), 1.87-1.42 (m, 4H);MS (ESI) m/z 169 [M+H]⁺

Step B: A mixture of 9-methyl-9-aza-bicyclo[3.3.1]nonan-3-one oximehydrochloride (0.670 g, 3.27 mmol), rhodium on carbon (0.610 g, 5%rhodium), methanol (18 mL), and concentrated ammonium hydroxide (8.0 mL,120 mmol) was shaken under a 50 psi hydrogen atmosphere and warmed to50° C. for 19 h. The mixture was then filtered through a pad ofdiatomaceous earth and the pad rinsed with additional methanol (3×20mL). The filtrate was then concentrated to dryness, and residue waspartitioned between 10% aqueous sodium carbonate (25 mL) and chloroform(25 mL). The layers were separated, and the aqueous layer was extractedwith additional chloroform (2×25 mL). The combined organic extracts weredried over anhydrous potassium carbonate, filtered, and concentrated toafford 3-amino-9-methyl-9-azabicyclo[3.3.1]nonane (0.466 g, 92% yield)as a yellow oil: ¹H NMR (500 MHz, CDCl₃) d 3.20 (m, 1H), 3.01 (d, J=11.1Hz, 2H), 2.46 (s, 3H), 2.32-2.25 (m, 2H), 1.99-1.89 (m, 3H), 1.50-1.42(m, 1H), 1.14-10.9 (m, 2H), 1.07 (br s, 2H), 0.98-0.91 (m, 2H); MS (ESI)m/z 155 [M+H]⁺. This material was converted to the correspondingdihydrochloride salt in quantitative yield by treatment with excess 4Mhydrogen chloride gas in dioxane: mp 232-235° C. ¹H NMR (300 MHz,DMSO-d₆) δ 11.28 (br s, 1H), 10.31 (br s, 1H), 8.46 (br s, 2H), 3.85 (brs, 2H), 3.61 (br s, 1H), 3.07 (dd, J=18.1, 6.6 Hz, 1H), 2.96 (d, J=4.6Hz, 2H), 2.76 (d, J=4.6 Hz, 1H), 2.46 (d, J=17.0 Hz, 1H), 2.30-2.18 (m,2H), 2.02 (br d, J=7.8 Hz, 1H), 1.88-1.72 (m, 2H), 1.70-1.19 (m, 3H).

Step C:N-(9-Methyl-9-azabicyclo[3.3.1]non-3-yl)-2-phenylbenzoxazole-4-carboxamidewas prepared from 3-amino-9-methyl-9-azabicyclo[3.3.1]nonanedihydrochloride and 2-phenylbenzoxazole-4-carboxylic acid usingconditions similar to those described for Step C in Example 1. Thiscompound was obtained in 40% yield as a white solid; mp 182-185° C.; ¹HNMR (300 MHz, CDCl₃) δ 9.18 (d, J=6.5 Hz, 1H), 8.25 (m, 2H), 8.19 (dd,J=7.8, 0.9 Hz, 1H), 7.72 (dd, J=8.1, 1.0 Hz, 1H), 7.55-7.65 (m, 3H),7.47 (t, J=8.0 Hz, 1H), 4.71-4.58 (m, 1H), 3.30 (m, 2H), 2.76 (m, 2H),2.69 (s, 3H), 2.38-1.33 (m, 8H); MS (APCI) m/z 376 [M+H]⁺

Example 6 Preparation ofN-(8-Methyl-8-azabicyclo[3.2.1]oct-3-yl)-2-phenylbenzoxazole-4-carboxamide

Step A: A 500-mL one-neck round-bottomed flask equipped with a magneticstirrer was charged with 8-methyl-8-aza-bicyclo[3.2.1]octan-3-one (5.00g, 35.9 mmol), hydroxylamine hydrochloride (7.08 g, 102 mmol) sodiumacetate (39.0 g, 476 mmol) and ethanol (45 mL). After stirring atambient temperature for 4 h, the reaction mixture was evaporated to asolid residue. This residue was triturated with ethyl acetate (200 mL)and filtered. Evaporation of the filtrate to dryness gave 5.08 g (93%yield) of 8-methyl-8-aza-bicyclo[3.2.1]octan-3-one oxime as a whitesolid: mp 140-142° C.; ¹H NMR (300 MHz, CD₃OD) δ 3.76 (m, 2H), 3.33-3.23(m, 2H), 2.75 (m, 1H), 2.69 (s, 3H), 2.46-2.14 (m, 4H), 1.88-1.66 (m,2H); MS (APCI) m/z 155 [M+H]⁺.

Step B: A 500-mL Parr hydrogenation vessel was purged with nitrogen andcharged with platinum (IV) oxide (1.28 g, 5.64 mmol),8-methyl-8-aza-bicyclo[3.2.1]octan-3-one oxime (4.00 g, 26.0 mmol),acetic acid (11 mL) and ethanol (110 mL). The bottle was evacuated,charged with hydrogen gas to a pressure of 50 psi and shaken for 24 h ona Parr hydrogenation apparatus. The hydrogen was then evacuated andnitrogen charged to the bottle. The reaction mixture was then mixed withCelite 521 (5.0 g), filtered, and the filtrate evaporated to a solidresidue. This residue was dissolved in methanol (100 mL) and thissolution treated with sodium carbonate (10 g). The resulting suspensionwas added diethyl ether (50 mL) and filtered. Evaporation of thefiltrate to dryness afforded 3.64 g (100%) of8-methyl-8-azabicyclo[3.2.1]oct-3-ylamine as a white solid: ¹H NMR (300MHz, CD₃OD) δ 5.18 (br s, 2H), 3.35 (br s, 2H), 3.21 (t, J=6.6 Hz, 1H),2.40 (s, 3H), 2.26-2.00 (m, 6H), 1.68-1.58 (m, 2H).

Step C:N-(8-Methyl-8-azabicyclo[3.2.1]oct-3-yl)-2-phenylbenzoxazole-4-carboxamidewas prepared from 3-amino-8-methyl-8-azabicyclo[3.2.1]octane and2-phenylbenzoxazole-4-carboxylic acid using conditions similar to thosedescribed for Step C in Example 1. This compound was obtained in 25%yield as a white solid; mp 149-151° C.; ¹H NMR (300 MHz, CDCl₃) δ 9.55(d, J=7.6 Hz, 1H), 8.29 (m, 2H), 8.22 (dd, 1H, J=7.8, 1.0 Hz, 1H), 7.72(dd, J=8.1, 1.0 Hz, 1H), 7.65-7.55 (m, 3H), 7.47 (t, J=8.0 Hz, 1H), 4.48(q, 1H, J=7.2 Hz), 3.25 (br s, 2H), 2.43-2.24 (m, 9H), 1.87 (d, J=14.2Hz, 2H); MS (APCI) m/z 362 [M+H]⁺.

Example 7 Preparation ofN-(9-Methyl-9-azabicyclo[3.3.1]non-3-yl)-6-chloro-2-phenylbenzoxazole-4-carboxamide

Step A: A 25-mL round bottomed flask equipped with a magnetic stirrerwas charged with 2-amino-3-hydroxybenzoic acid (0.852 g, 5.59 mmol),acetic acid (0.4 mL) and diethyl ether (0.4 mL). After cooling to 0° C.sulfuryl chloride (0.754 g, 5.59 mmol) was added and the reactionstirred at ambient temperature for 4 h. Dilution with ether (15 mL),filtration and purification by preparative HPLC afforded 0.500 g (48%yield) of 2-amino-5-chloro-3-hydroxybenzoic acid as a white solid: ¹HNMR (500 MHz, CD₃OD) δ 7.29 (d, J=9.5 Hz, 1H), 6.76 (d, 1H, J=9.5 Hz,1H) MS (ESI) m/z 186 (M−H).

Step B: A 25-mL, round bottomed flask equipped with a magnetic stirrerwas charged with 2-amino-5-chloro-3-hydroxybenzoic acid (0.931 g, 4.96mmol), trimethyl orthobenzoate (7.23 g, 39.7 mmol), and pyridiniump-toluenesulfonate (0.062 g, 0.248 mmol). After stirring at 90° C. for 1h, the reaction was diluted with hexanes (30 mL) filtered, and thefilter cake dried in a vacuum oven at 40° C. to afford 0.455 g (33%yield) of 6-chloro-2-phenyl-benzoxazole-4-carboxylic acid as a brownsolid: ¹H NMR (500 MHz, DMSO-d₆) δ 8.24 (m, 3H), 7.84 (s, 1H), 7.65 (m,3H); MS (ESI) m/z 272 (M−H).

Step C: A 15-mL, round bottomed flask equipped with a magnetic stirrerwas purged with nitrogen and charged with6-chloro-2-phenyl-benzoxazole-4-carboxylic acid (0.075 g, 0.274 mmol),3-amino-9-methyl-9-azabicyclo[3.3.1]nonane dihydrochloride (0.063 g,0.411 mmol) 1-ethyl-3-[3-(dimethylamino)propyl]carbodiimidehydrochloride (0.079 g, 0.411 mmol), 1-hydroxybenzotriazole (0.037 g,0.274 mmol), diisopropylethylamine (0.141 g, 1.09 mmol), and DMF (1.0mL). After stirring at ambient temperature for 18 h, the reaction wasconcentrated under reduced pressure and purified by preparative HPLC toafford 0.016 g (14% yield) ofN-(9-methyl-9-azabicyclo[3.3.1]non-3-yl)-6-chloro-2-phenylbenzoxazole-4-carboxamideas an off-white solid: ¹H NMR (500 MHz, CDCl₃) δ 8.95 (br s, 1H), 8.23(d, J=6.9 Hz, 2H), 8.20 (d, J=2.0 Hz, 1H), 7.71 (d, J=2.0 Hz, 1H),7.65-7.57 (m, 3H), 4.58 (q, J=7.1 Hz, 1H), 3.18 (br s, 2H), 2.58 (m,5H), 2.25-2.02 (m, 3H), 1.55 (s, 3H), 1.23 (m, 3H); MS (APCI) m/z 409[M+H]⁺

Example 8 Preparation ofN-(Piperidin-4-yl)-2-phenylbenzoxazole-4-carboxamide

N-(1-tert-butyloxycarbonylpiperidin-4-yl)-2-phenylbenzoxazole-4-carboxamidewas prepared from 4-amino-1-tert-butyloxycarbonylpiperidine and2-phenylbenzoxazole-4-carboxylic acid using the coupling methoddescribed in Step C of Example 7. This crude material was immediatelydissolved in a mixture of trifluoroacetic acid (1.0 mL) and water (0.05mL) and the resulting solution stirred at ambient temperature for 0.5hours. The reaction was then concentrated to dryness in vacuo. Theresulting oil was purified using preparative HPLC to afford a 74% yieldof N-(piperidin-4-yl)-2-phenylbenzoxazole-4-carboxamide as a whitesolid: mp 99-102° C.; ¹H NMR (500 MHz, CD₃OD) δ 8.27 (dd, J=7.5, 2.0 Hz,2H), 7.89 (dd, J=8.0, 1.0 Hz, 1H), 7.78 (d, J=8.0 Hz, 1H), 7.65-7.58 (m,3H), 7.49 (t, J=8.0 Hz, 1H), 4.20-4.14 (m, 1H), 3.26 (d, J=13.0 Hz, 2H),2.90 (t, J=12.0 Hz, 2H), 2.16 (d, J=12.5 Hz, 2H), 1.75 (q, J=12.5 Hz,2H); MS (ESI) m/z 322 [M+H]⁺.

Example 9 Preparation ofN-(1-Azabicyclo[2.2.2]oct-3-yl)-2-phenylbenzoxazole-4-carboxamide

N-(1-Azabicyclo[2.2.2]oct-3-yl)-2-phenylbenzoxazole-4-carboxamide wasprepared from 2-phenylbenzoxazole-4-carboxylic acid and3-aminoquinuclidine dihydrochloride using the method outlined in Step Cof Example 7. This compound was obtained in 51% yield as an off-whitesolid: mp 77-80° C.; ¹H NMR (500 MHz, CDCl₃) δ 9.58 (d, J=7.1 Hz, 1H),8.24 (d, J=5.2 Hz, 2H), 8.19 (d, 1H, J=6.8 Hz, 1H), 7.72 (d, J=7.1 Hz,1H), 7.61-7.49 (m, 3H), 7.48 (t, J=7.9 Hz, 1H), 4.31 (m, 1H), 3.51 (dd,J=7.1, 2.3 Hz, 1H), 3.10 (m, 2H), 2.91 (m, 2H), 2.83 (dd, J=10.1, 4.2Hz, 1H), 2.16 (m, 1H), 2.05 (m, 1H), 1.65-1.43 (m, 3H); MS (APCI) m/z348 [M+H]⁺

Example 10 Preparation ofN-(1-Methyl-piperidin-4-yl)-6-chloro-2-phenylbenzoxazole-4-carboxamide

This material was prepared from6-chloro-2-phenyl-benzoxazole-4-carboxylic acid and4-amino-1-methylpiperdine using the method outlined in Step C of Example7. This compound was obtained in 46% yield as a tan solid: mp 170-172°C.; ¹H NMR (300 MHz, CDCl₃) δ 9.14 (d, J=7.8 Hz, 1H), 8.23 (dd, J=6.6,1.5 Hz, 2H), 8.18 (d, J=1.5 Hz, 1H), 7.71 (d, J=2.1 Hz, 1H), 7.65-7.54(m, 3H), 4.19-4.13 (m, 1H), 2.87 (d, J=1.5 Hz, 2H), 2.37 (s, 3H),2.32-2.26 (m, 2H), 2.17-2.13 (m, 2H), 1.84-1.72 (m, 2H); MS (ESI) m/z370 [M+H]⁺

Example 11 Preparation ofN-(Piperidin-4-yl)-6-chloro-2-phenylbenzoxazole-4-carboxamide

N-(1-tert-butyloxycarbonylpiperidin-4-yl)-6-chloro-2-phenylbenzoxazole-4-carboxamidewas prepared from 4-amino-1-tert-butyloxycarbonylpiperidine and2-phenylbenzoxazole-4-carboxylic acid using the method described in StepC of Example 7. The crude product was immediately dissolved in a mixtureof trifluoroacetic acid (1.0 mL) and water (0.05 mL) and the resultingsolution stirred at ambient temperature for 0.5 hours. The reaction wasthen concentrated to dryness in vacuo. The resulting oil was purifiedusing preparative HPLC to afford a 89% yield ofN-(piperidin-4-yl)-6-chloro-2-phenylbenzoxazole-4-carboxamide as a whitesolid: mp 169-171° C.; ¹H NMR (500 MHz, CDCl₃) δ 9.12 (d, J=7.5 Hz, 1H),8.24 (d, J=7.1 Hz, 2H), 8.18 (d, J=2.0 Hz, 1H), 7.71 (d, J=2.0 Hz, 1H),7.64-7.56 (m, 3H), 4.43 (m, 1H), 3.19 (dt, J=5.1, 3.6 Hz, 2H), 2.87 (t,J=10.5 Hz, 2H), 2.06 (m, 2H), 1.63 (m, 2H); MS (APCI) m/z 357 [M+H]⁺.

Example 12 Preparation ofN-(1-Azabicyclo[2.2.2]oct-3-yl)-6-chloro-2-phenylbenzoxazole-4-carboxamide

N-(1-Azabicyclo[2.2.2]oct-3-yl)-6-chloro-2-phenylbenzoxazole-4-carboxamidewas prepared from 6-chloro-2-phenyl-benzoxazole-4-carboxylic acid and3-aminoquinuclidine dihydrochloride using the method outlined in Step Cof Example 7. This compound was obtained in 24% yield as a white solid:mp 180-183° C.; ¹H NMR (500 MHz, CDCl₃) δ 9.45 (d, J=7.3 Hz, 1H), 8.22(d, J=5.0 Hz, 2H), 8.18 (d, J=2.0 Hz, 1H), 7.72 (d, J=2.0 Hz, 1H),7.64-7.47 (m, 3H), 4.29 (m, 1H), 3.51 (dd, J=7.2, 2.1 Hz, 1H), 3.05 (m,2H), 2.91 (m, 2H), 2.80 (dd, J=10.2, 4.0 Hz, 1H), 2.15 (m, 1H), 2.04 (m,1H), 1.78-1.60 (m, 3H); MS (APCI) m/z 382 [M+H]⁺

Example 13 Preparation ofN-(8-Methyl-8-azabicyclo[3.2.1]oct-3-yl)-6-chloro-2-phenylbenzoxazole-4-carboxamide

N-(8-Methyl-8-azabicyclo[3.2.1]oct-3-yl)-6-chloro-2-phenylbenzoxazole-4-carboxamidewas prepared from 6-chloro-2-phenyl-benzoxazole-4-carboxylic acid and3-amino-8-methyl-8-azabicyclo[3.2.1]octane using the method outlined inStep C of Example 7. This compound was obtained in 20% yield as a whitesolid: mp 187-190° C.; ¹H NMR (500 MHz, CDCl₃) δ 9.44 (d, J=7.5 Hz, 1H),8.26 (d, J=7.1 Hz, 2H), 8.21 (d, J=2.0 Hz, 1H), 7.72 (d, J=2.0 Hz, 1H),7.65-7.47 (m, 3H), 4.46 (q, J=7.2 Hz, 1H), 3.25 (br s, 1H), 2.38 (m,5H), 2.26 (m, 4H), 1.84 (d, J=14.3 Hz, 2H), 2.15 (m, 1H), 2.04 (m, 1H),1.78-1.60 (m, 3H); MS (APCI) m/z 397 [M+H]⁺

Example 14 Preparation ofN-(1-Azabicyclo[2.2.2]oct-3-yl)-2-(4-chlorophenyl)benzoxazole-4-carboxamide

Step A: 2-(4-Chlorophenyl)benzoxazole-4-carboxylic acid was preparedfrom 3-hydroxyanthranilic acid and 4-chlorobenzoyl chloride using themethod described in Step A of Example 1. This crude material (2.90 g,10.6 mmol) was directly dissolved in DMF (40 mL), DIPEA (5.46 g, 42.4mmol) and methyl iodide (5.93 g, 42.4 mmol) added and the reactionstirred at room temperature for 18 h. After this time the reaction wasdiluted with ethyl acetate (100 mL) and 2 N HCl (50 mL). The organiclayer was separated and then washed with 2 N HCl (25 mL), water (50 mL)and brine (50 mL). The organic layer was then dried over sodium sulfate,filtered and concentrated to dryness to yield light yellow oil. Thismaterial was purified using silica gel chromatography to afford 0.532 g(30% yield) of methyl 2-(4-chlorophenyl)benzoxazole-4-carboxylate as awhite solid: ¹H NMR (300 MHz, CDCl₃) δ 8.28 (dd, J=6.9, 1.8 Hz, 2H),8.04 (d, J=8.1 Hz, 1H), 7.78 (d, J=8.1 Hz, 1H), 7.52 (d, J=8.7 Hz, 2H),7.43 (t, J=7.8 Hz, 1H), 4.06 (s, 3H); MS (ESI) m/z 288 [M+H]⁺

Step B: A 100 mL round bottom flask equipped with a magnetic stirrer wascharged with methyl 2-(4-chlorophenyl)benzoxazole-4-carboxylate (0.50 g,1.74 mmol), THF (10 mL), methanol (10 mL), lithium hydroxide (0.08 g,3.48 mmol) and water (10 mL). The reaction was stirred at roomtemperature for 18 hours. After this time, the reaction was diluted withethyl acetate (50 mL) then acidified to pH 4 with 2 N HCl. The aqueouslayer was extracted with ethyl acetate (2×25 mL). The organic layerswere then combined and washed with brine (1×25 mL), dried with sodiumsulfate, filtered and concentrated to dryness in vacuo to yield2-(4-chlorophenyl)benzoxazole-4-carboxylic acid (0.43 g, 90% yield) as awhite solid: ¹H NMR (500 MHz, CDCl₃) δ 11.53 (bs, 1H), 8.26 (d, J=8.5Hz, 2H), 8.18 (d, J=8.0 Hz, 1H), 7.84 (d, J=8.0 Hz, 1H), 7.58 (d, J=8.5Hz, 2H), 7.55 (t, J=8.0 Hz, 1H); MS (ESI) m/z 274 [M+H]⁺

Step C: A 25 mL round bottomed flask equipped with a reflux condenserwas purged with nitrogen and charged with2-(4-chlorophenyl)benzoxazole-4-carboxylic acid (0.050 g, 0.18 mmol)followed by thionyl chloride (5 mL). The resulting suspension was heatedto reflux for 1 hr, after which time a light yellow solution wasobtained. The reaction was then cooled and the thionyl chloride removedunder reduced pressure affording an off-white solid. This solid wasdissolved in methylene chloride (10 mL) and quinuclidine dihydrochloride(0.056 g, 0.27 mmol) added followed by the drop-wise addition ofdiisopropylethylamine (0.371 g, 2.87 mmol) over 5 min. After stirring atroom temperature for 3 hrs the reaction was quenched by the addition ofwater (10 mL) and the organic layer separated. Subsequent washing of theorganic layer with water (10 mL) followed by brine (10 mL), drying overMgSO₄, filtration and concentration afforded a tan solid. This solid waspurified by preparative HPLC to afford 0.012 g (17% yield) ofN-(1-azabicyclo[2.2.2]oct-3-yl)-2-(4-chlorophenyl)benzoxazole-4-carboxamideas an white solid: mp 194-196° C.; ¹H NMR (500 MHz, DMSO-d₆) δ 9.13 (m,1H), 8.23 (dd, J=6.7, 1.9 Hz, 2H), 8.03 (dd, J=8.2, 0.9 Hz, 1H), 7.97(dd, J=7.7, 0.9 Hz, 1H), 7.78 (dd, J=6.7, 1.9 Hz, 2H), 7.58 (t, J=8.0Hz, 1H), 4.09 (m, 1H), 3.28 (m, 1H), 2.85 (m, 2H), 2.75 (m, 2H), 2.63(m, 1H), 2.08 (m, 1H), 1.99 (m, 1H), 1.65 (m, 2H), 1.57 (m, 1H); MS(ESI) m/z 382 [M+H]⁺.

Example 15 Preparation ofN-(9-Methyl-9-azabicyclo[3.3.1]non-3-yl)-2-(4-chlorophenyl)benzoxazole-4-carboxamide

N-(9-Methyl-9-azabicyclo[3.3.1]non-3-yl)-2-(4-chlorophenyl)benzoxazole-4-carboxamidewas prepared from 2-(4-chlorophenyl)benzoxazole-4-carboxylic acid and3-amino-9-methyl-9-azabicyclo[3.3.1]nonane dihydrochloride using themethod outlined in Step C of Example 14. This compound was obtained in16% yield as a white solid: mp 185-187° C.; ¹H NMR (500 MHz, DMSO-d₆) δ8.72 (d, J=7.7 Hz, 1H), 8.27 (d, J=8.5 Hz, 2H), 7.99 (d, J=8.1 Hz, 1H),7.98 (d, J=8.1 Hz, 1H), 7.76 (d, J=8.5 Hz, 2H), 7.56 (t, J=8.0 Hz, 1H),4.01 (m, 1H), 3.02 (m, 2H), 2.44 (s, 3H), 2.41 (m, 2H), 2.09 (m, 1H),1.97 (m, 2H), 1.47 (m, 3H), 1.00 (m, 2H); MS (ESI) m/z 410 [M+H]⁺

Example 16 Preparation ofN-(1-Azabicyclo[2.2.2]oct-3-yl)-2-(4-methoxyphenyl)benzoxazole-4-carboxamide

Step A: Methyl 2-(4-methoxyphenyl)benzoxazole-4-carboxylate was preparedfrom methyl 3-hydroxyanthranilate and 4-methoxybenzoyl chloride asdescribed in Step A of Example 1. The product was obtained as anoff-white solid in 18% yield. δ 8.29 (m, 2H), 8.01 (dd, J=7.8, 1.0 Hz,1H), 7.74 (dd, J=8.1, 1.0 Hz, 1H), 7.37 (t, J=7.9 Hz, 1H), 7.03 (m, 2H),4.06 (s, 3H); 3.91 (s, 3H); MS (ESI) m/z 284 [M+H]⁺.

Step B: 2-(4-Methoxyphenyl)benzoxazole-4-carboxylic acid was preparedvia the lithium hydroxide mediated hydrolysis of methyl2-(4-methoxyphenyl)benzoxazole-4-carboxylate as described in Step B ofExample 14. This material was obtained in 92% yield as a white solid: δ11.90 (br s, 1H), 8.25 (m, 2H), 8.13 (dd, J=7.8, 0.9 Hz, 1H), 7.79 (dd,J=7.8, 0.9 Hz, 1H), 7.48 (t, J=7.9 Hz, 1H), 7.08 (m, 2H), 3.93 (s, 3H);MS (ESI) m/z 270 [M+H]⁺

Step C:N-(1-Azabicyclo[2.2.2]oct-3-yl)-2-(4-methoxyphenyl)benzoxazole-4-carboxamidewas prepared from 2-(4-methoxyphenyl)benzoxazole-4-carboxylic acid and3-aminoquinuclidine dihydrochloride using the method outlined in Step Cof Example 14. This compound was obtained in 5% yield as an off-whitesolid: mp 108-109° C.; ¹H NMR (500 MHz, CD₃OD) δ 8.19 (dt, J=9.7, 2.8Hz, 2H), 8.01 (dd, J=7.7, 0.9 Hz, 1H), 7.82 (dd, J=7.7, 0.9 Hz, 1H),7.49 (t, J=8.0 Hz, 1H), 7.14 (dt, J=9.7, 2.8 Hz, 2H), 4.25 (m, 1H), 3.91(s, 3H), 3.47 (m, 1H), 3.02 (m, 2H), 2.91 (m, 2H), 2.77 (m, 1H), 2.12(m, 2H), 1.80 (m, 3H); MS (ESI) m/z 378 [M+H]⁺

Example 17 Preparation ofN-(9-Methyl-9-azabicyclo[3.3.1]non-3-yl)-2-(4-methoxyphenyl)benzoxazole-4-carboxamide

N-(9-Methyl-9-azabicyclo[3.3.1]non-3-yl)-2-(4-methoxyphenyl)benzoxazole-4-carboxamidewas prepared from 2-(4-methoxyphenyl)benzoxazole-4-carboxylic acid and3-amino-9-methyl-9-azabicyclo[3.3.1]nonane dihydrochloride using themethod outlined in Step C of Example 14. This compound was obtained in60% yield as a white solid: mp 103-105° C.; ¹H NMR (500 MHz, CDCl₃) δ9.07 (m, 1H), 8.19 (m, 3H), 7.66 (dd, J=8.0, 1.1 Hz, 1H), 7.41 (t, J=7.9Hz, 1H), 7.07 (m, 2H), 4.60 (m, 1H), 3.92 (s, 3H), 3.11 (m, 2H), 2.66(m, 2H), 2.54 (s, 3H), 2.13 (m, 1H), 2.03 (m, 2H), 1.53 (m, 3H), 1.17(m, 2H); MS (ESI) m/z 406 [M+H]⁺

Example 18 Preparation ofN-(9-Methyl-9-azabicyclo[3.3.1]non-3-yl)-2-(4-fluorophenyl)benzoxazole-4-carboxamide

Step A: 2-(4-fluorophenyl)benzoxazole-4-carboxylic acid was preparedfrom 3-hydroxyanthranilic acid and 4-fluorobenzoyl chloride as describedin Step A of Example 1. The crude product was dissolved in methylenechloride (20 mL) and the resulting solution treated with oxalyl chloride(1 mL) and DMF (0.05 mL). After stirring at room temperature for 6 h,the reaction was quenched by the addition of methanol (10 mL) andstirred at room temperature for a further 71 h. The reaction was thenre-concentrated and the resulting solid purified by columnchromatography to afford a 26% yield of methyl2-(4-fluorophenyl)benzoxazole-4-carboxylate as a white solid: ¹H NMR(500 MHz, CDCl₃) δ 8.36 (dd, J=14.7, 11.8 Hz, 2H), 8.03 (d, J=14.7 Hz,1H), 7.78 (d, J=15.2 Hz, 1H), 7.42 (t, J=13.2 Hz, 1H), 7.18 (m, 2H),4.06 (m, 3H).

Step B: 2-(4-Fluorophenyl)benzoxazole-4-carboxylic acid was prepared viathe lithium hydroxide mediated hydrolysis of methyl2-(4-fluorophenyl)benzoxazole-4-carboxylate as described in Step B ofExample 14. This material was obtained in 60% yield as a white solid: ¹HNMR (500 MHz, CDCl₃) δ 8.32 (dd, J=14.9, 11.8 Hz, 2H), 8.17 (d, J=13.1Hz, 1H), 7.83 (d, J=13.6 Hz, 1H), 7.53 (t, J=13.4 Hz, 1H), 7.29 (m, 2H).MS (ESI) m/z 258 [M+H]⁺

Step C:N-(9-Methyl-9-azabicyclo[3.3.1]non-3-yl)-2-(4-fluorophenyl)benzoxazole-4-carboxamidewas prepared from 2-(4-fluorophenyl)benzoxazole-4-carboxylic acid and3-amino-9-methyl-9-azabicyclo[3.3.1]nonane dihydrochloride using themethod outlined in Step C of Example 14. This compound was obtained in60% yield as a white solid: mp 197-199° C.; ¹H NMR (500 MHz, CDCl₃) δ8.95 (m, 1H), 8.26 (m, 2H), 8.21 (dd, J=7.8, 1.0 Hz, 1H), 7.69 (dd,J=8.1, 1.0 Hz, 1H), 7.46 (t, J=7.9 Hz, 1H), 7.29 (m, 1H), 4.60 (m, 1H),3.11 (m, 2H), 2.66 (m, 2H), 2.54 (s, 3H), 2.15 (m, 1H), 2.04 (m, 2H),1.59 (m, 2H), 1.51 (m, 2H), 1.17 (m, 2H); MS (ESI) m/z 394 [M+H]⁺

Example 19 Preparation ofN-(1-Azabicyclo[2.2.2]oct-3-yl)-2-(4-fluorophenyl)benzoxazole-4-carboxamide

N-(1-Azabicyclo[2.2.2]oct-3-yl)-2-(4-fluorophenyl)benzoxazole-4-carboxamidewas prepared from 2-(4-fluorophenyl)benzoxazole-4-carboxylic acid and3-aminoquinuclidine dihydrochloride using the method outlined in Step Cof Example 14. This compound was obtained in 8% yield as a white solid:mp 208-209° C.; ¹H NMR (500 MHz, CD₃OD) δ 8.33 (m, 2H), 8.05 (m, 1H),7.90 (dd, J=8.2, 0.9 Hz, 1H), 7.55 (m, 1H), 7.39 (m, 2H), 4.29 (m, 1H),3.52 (m, 1H), 3.06 (m, 2H), 2.94 (m, 2H), 2.92 (m, 1H), 2.16 (m, 2H),1.86 (m, 3H); MS (ESI) m/z 366 [M+H]⁺

Example 20 Preparation ofN-(9-Methyl-9-azabicyclo[3.3.1]non-3-yl)-2-phenylbenzoxazole-7-carboxamide

Step A: 2-Phenylbenzoxazole-7-carboxylic acid was prepared from3-aminosalicyclic acid and benzoyl chloride using a procedure identicalto that described in Step A of Example 1. This material was obtained in86% yield as an off-white solid: ¹H NMR (500 MHz, CD₃OD) δ 8.30 (dd,J=7.2, 2.1 Hz, 2H), 7.98 (dd, J=12.9, 7.8 Hz, 2H), 7.60(m, 3H), 7.48 (t,J=7.8 Hz, 1H); MS (APCI) m/z 240 [M+H]⁺

Step B:N-(9-Methyl-9-azabicyclo[3.3.1]non-3-yl)-2-phenylbenzoxazole-7-carboxamidewas prepared from 2-phenylbenzoxazole-7-carboxylic acid and3-amino-9-methyl-9-azabicyclo[3.3.1]nonane dihydrochloride using themethod outlined in Step C of Example 7. This compound was obtained in43% yield and obtained as an off-white solid: mp 208-210° C.; ¹H NMR(500 MHz, CDCl₃) δ 8.95 (br s, 1H), 8.23 (d, J=6.9 Hz, 2H), 8.20(d,J=2.0 Hz, 1H), 7.71 (d, J=2.0 Hz, 1H), 7.57-7.65 (m, 3H), 4.58 (q, J=7.1Hz, 1H), 3.18 (br s, 2H), 2.58 (m, 5H), 2.02-2.25 (m, 3H), 1.55 (s, 3H),1.23 (m, 3H); MS (APCI) m/z 411 [M+H]⁺

Example 21 Preparation ofN-(1-Methylpiperidin-4-yl)-2-phenylbenzoxazole-7-carboxamide

N-(1-Methylpiperidin-4-yl)-2-phenylbenzoxazole-7-carboxamide wasprepared from 2-phenylbenzoxazole-7-carboxylic acid and4-amino-1-methylpiperidine using the method outlined in Step C ofExample 7. This compound was obtained in 58% yield and obtained as awhite solid: mp 209-210° C.; ¹H NMR (300 MHz, CDCl₃) δ 8.22 (m, 1H),8.21 (dd, J=5.7, 1.8 Hz, 1H), 8.10 (dd, J=8.1, 0.9 Hz, 1H), 7.91 (dd,J=9.9, 1.2 Hz, 1H), 7.64-7.54 (m, 3H), 7.48 (t, J=7.8, 1H), 4.26-4.17(m, 1H), 2.93 (d, J=11.4 Hz, 2H), 2.46 (s, 3H), 2.30 (t, J=11.1 Hz, 2H),2.22-2.17 (m, 2H), 1.85-1.73 (m, 2H); MS (ESI) m/z 336 [M+H]⁺

Example 22 Preparation ofN-(Piperidin-4-yl)-2-phenylbenzoxazole-7-carboxamide

N-(1-tert-butyloxycarbonylpiperidin-4-yl)-2-phenylbenzoxazole-7-carboxamidewas prepared from 4-amino-1-tert-butyloxycarbonylpiperidine using thecoupling method described in Step C of Example 7. This crude materialwas immediately dissolved in trifluoroacetic acid (1.0 mL) and water(0.05 mL) and the resulting solution stirred at ambient temperature for0.5 hours. The reaction was then concentrated to dryness in vacuo. Theresulting oil was purified using preparative HPLC to afford a 51% yieldofN-(1-tert-butyloxycarbonylpiperidin-4-yl)-2-phenylbenzoxazole-7-carboxamideas a white solid: mp 191-193° C.; ¹H NMR (500 MHz, CD₃OD) δ 8.27 (m,1H), 8.26 (dd, J=8.5, 2.0 Hz, 1H), 7.89 (d, J=7.5 Hz, 1H), 7.78 (d,J=7.5 Hz, 1H), 7.64-7.58 (m, 3H), 7.48 (t, J=8.0 Hz, 1H), 4.14-4.06 (m,1H), 3.13 (d, J=13.0 Hz, 2H), 2.75 (t, J=12.5 Hz, 2H), 2.08 (d, J=12.0Hz, 2H), 1.64 (q, J=8.5 Hz, 2H); MS (ESI) m/z 320 [M+H]⁺

Example 23 Preparation ofN-(1-Azabicyclo[2.2.2]oct-3-yl)-2-phenylbenzoxazole-7-carboxamide

N-(1-Azabicyclo[2.2.2]oct-3-yl)-2-phenylbenzoxazole-7-carboxamide wasprepared from 2-phenylbenzoxazole-7-carboxylic acid and3-aminoquinuclidine dihydrochloride using the method outlined in Step Cof Example 7. This compound was obtained in 57% yield as a white solid:mp 179-180° C.; ¹H NMR (300 MHz, CDCl₃) δ 8.21 (dd, J=7.5, 2.1 Hz, 2H),8.10 (dd, J=7.8, 1.2 Hz, 1H), 7.92 (dd, J=7.8, 1.2 Hz, 1H), 7.61-7.54(m, 3H), 7.51-7.46 (m, 2H), 4.38-4.33 (m, 1H), 3.63-3.54 (m, 1H),3.13-3.05 (m, 2H), 2.23 (q, J=3.0 Hz, 1H), 2.00-1.90 (m, 1H), 1.84-1.73(m, 2H), 1.71-1.64 (m, 1H); MS (ESI) m/z 348[M+H]⁺.

Example 24 Preparation ofN-(8-Methyl-8-azabicyclo[3.2.1]oct-3-yl)-2-phenylbenzoxazole-7-carboxamide

N-(8-Methyl-8-azabicyclo[3.2.1]oct-3-yl)-2-phenylbenzoxazole-7-carboxamidewas prepared from 3-amino-8-methyl-8-azabicyclo[3.2.1]octane and2-phenylbenzoxazole-7-carboxylic acid using conditions similar to thosedescribed for Step C in Example 7. This compound was obtained in 57%yield as a white solid: mp 164-166° C.; ¹H NMR (300 MHz, CH₃OD) δ 8.25(dd, J=8.1, 1.8 Hz, 2H), 7.90 (dd, J=8.1, 1.2 Hz, 1H), 7.80 (d, J=7.5Hz, 1H), 7.64-7.58 (m, 3H), 7.50 (t, J=7.8 Hz, 1H), 4.25 (t, J=5.0 Hz,1H), 3.63 (br s, 2H), 2.63 (s, 3H), 2.53-2.35 (m, 6H), 2.22-2.17 (m,2H); MS (ESI) m/z 362 [M+H]⁺.

Example 25 Preparation ofN-(1-Azabicyclo[2.2.2]oct-3-yl)-5-chloro-2-phenyl-benzoxazole-7-carboxamide

Step A: A 250-mL single-neck round bottomed flask equipped with amagnetic stirrer was charged with methyl 4-chlorosalicylate (25.0 g, 134mmol) followed by concentrated sulfuric acid (73 mL) and the resultingsuspension cooled to 0° C. using an ice bath. Concentrated nitric acid(6.20 mL, 147 mmol) was then added and the reaction stirred for 1 h at0° C. After this time, the reaction was poured into ice and theresulting precipitate collected by vacuum filtration. The filter cakewas washed with water (20 mL) and then re-crystallized from hot ethanol(100 mL) to afford methyl 4-chloro-3-nitrosalicylate in 52% yield (16.0g) as white solid: ¹H NMR (300 MHz, CDCl₃) δ 8.15 (d, J=2.7 Hz, 1H),8.11 (d, J=2.7 Hz, 1H), 4.03 (s, 3H); MS (ESI) m/z 232 [M+H]⁺.

Step B: A 100-mL single-neck round bottomed flask equipped with amagnetic stirrer and reflux condenser was charged with methyl4-chloro-3-nitrosalicylate (1.00 g, 4.32 mmol), glacial acetic acid (23mL) and methanol (18 mL). The stirred solution was then treated with 325mesh iron powder (2.41 g, 43.2 mmol) and heated at reflux for 30 min.After this time, the reaction was cooled to room temperature andfiltered through a pad of celite 521. The pad was rinsed with methanol(10 mL) and the filtrates combined and partitioned between ethyl acetate(100 mL) and saturated aqueous sodium bicarbonate (50 mL). The organiclayer was separated and washed with water (2×100 mL) then dried oversodium sulfate. The suspension was filtered and the filtrate treatedwith decolorizing carbon (0.50 g) and warmed to reflux. The suspensionwas then re-filtered hot through a pad of celite 521 and the resultingfiltrate concentrated to dryness under reduced pressure to afford methyl3-amino-4-chlorosalicylate in 81% yield (0.70 g) as white solid: ¹H NMR(300 MHz, CDCl₃) δ 7.19 (d, J=2.7 Hz, 1H), 6.82 (d, J=2.1 Hz, 1H), 3.95(br s, 2H), 3.94 (s, 3H); MS (ESI) m/z 202 [M+H]⁺.

Step C: Methyl 5-chloro-2-phenylbenzoxazole-7-carboxylate was preparedfrom methyl 3-amino-4-chlorosalicylate and trimethyl orthobenzoate asdescribed in Step B of Example 7. This material was obtained as whiteneedles in 99% yield. ¹H NMR (300 MHz, CDCl₃) δ 8.30 (dd, J=8.1, 2.1 Hz,2H), 7.94 (dd, J=13.8, 2.1 Hz, 2H), 7.59-7.55 (m, 3H), 4.07 (s, 3H); MS(ESI) m/z 288 [M+H]⁺

Step D: 5-Chloro-2-phenylbenzoxazole-7-carboxylic acid was prepared frommethyl 5-chloro-2-phenyl-benzoxazole-7-carboxylate via lithium hydroxidemediated hydrolysis as described in Step B of Example 14. This materialwas obtained as a white solid in 82% yield. ¹H NMR (300 MHz, DMSO-d₆) δ13.84 (br s, 1H), 8.22-8.19 (m, 3H), 7.85 (d, J=2.1 Hz, 1H), 7.70-7.63(m, 3H), 4.07 (s, 3H); MS (ESI) m/z 274 [M+H]⁺.

Step E:N-(1-Azabicyclo[2.2.2]oct-3-yl)-5-chloro-2-phenylbenzoxazole-7-carboxamidewas prepared from 5-chloro-2-phenyl-benzoxazole-7-carboxylic acid and3-aminoquinuclidine dihydrochloride using the method outlined in Step Cof Example 7. This compound was obtained in 56% yield as a white solid:mp 283-285° C.; ¹H NMR (300 MHz, CH₃OD) δ 8.22 (dd, J=8.1, 1.5 Hz, 2H),7.86 (d, J=2.1 Hz, 1H), 7.70 (d, J=2.1 Hz, 1H), 7.64-7.56 (m, 3H),4.27-4.24 (m, 1H), 3.50-3.42 (m, 1H), 3.12-2.86 (m, 5H), 2.17 (q, J=3.0Hz, 1H), 2.11-2.06 (m, 1H), 1.85-1.73 (m, 2H), 1.74-1.67 (m, 1H); MS(ESI) m/z 382[M+H]⁺.

Example 26 Preparation ofN-(9-Methyl-9-azabicyclo[3.3.1]non-3-yl)-5-chloro-2-phenyl-benzoxazole-7-carboxamide

N-(9-Methyl-9-azabicyclo[3.3.1]non-3-yl)-5-chloro-2-phenyl-benzoxazole-7-carboxamidewas prepared from 5-chloro-2-phenyl-benzoxazole-7-carboxylic acid and3-amino-9-methyl-9-azabicyclo[3.3.1]nonane dihydrochloride using themethod outlined in Step C of Example 7. This compound was obtained in49% yield as a white solid: mp 199-201° C.; ¹H NMR (300 MHz, CDCl₃) δ8.19 (dd, J=7.5, 2.1 Hz, 2H), 8.05 (d, J=2.1 Hz, 1H), 7.85 (d, J=2.1 Hz,1H), 7.66-7.55 (m, 3H), 6.84 (d, J=7.8 Hz, 1H), 4.65-4.56 (m, 1H), 3.15(d, J=10.5 Hz, 2H), 2.71-2.60 (m, 2H), 2.53 (s, 3H), 2.17-2.10 (m, 1H),2.03 (d, J=6.6 Hz, 3H), 1.78 (br s, 1H), 1.60-1.52 (m, 1H), 1.41 (t,J=10.8 Hz, 2H), 1.16-1.10 (m, 2H); MS (ESI) m/z 410 [M+H]⁺.

Example 27 Preparation ofN-(1-Azabicyclo[2.2.2]oct-3-yl)-2-(4-fluorophenyl)benzoxazole-7-carboxamide

Step A: Methyl 2-(4-fluorophenyl)benzoxazole-7-carboxylate was preparedfrom 3-aminosalicyclic acid and 4-fluorobenzoyl chloride in 28% yieldusing the procedure described in Step A in Example 14. ¹H NMR (500 MHz,CDCl₃) δ 8.32 (dd, J=14.9, 9.0 Hz, 2H), 7.98 (dd J=14.9, 9.0 Hz, 2H),7.43 (t, J=13.1 Hz, 1H), 7.26 (m, 2H), 4.06 (s, 3H); MS (ESI) m/z 272[M+H]⁺

Step B: 2-(4-Fluorophenyl)benzoxazole-7-carboxylic acid was prepared viathe lithium hydroxide mediated hydrolysis of methyl2-(4-fluorophenyl)benzoxazole-7-carboxylate as described in Step B ofExample 14. This material was obtained in quantitative yield as a whitesolid: ¹H NMR (500 MHz, DMSO-d₆) δ 8.25 (dd, J=14.8, 8.9 Hz, 2H), 8.07(dd, J=13.1, 1.6 Hz, 1H), 7.92 (dd, J=13.1, 1.6 Hz, 1H), 7.51 (m, 3H);MS (ESI) m/z 258 [M+H]⁺.

Step C: A solution of 2-(4-fluorophenyl)benzoxazole-7-carboxylic acid(0.100 g, 0.39 mmol) in acetonitrile (10 mL) was treated with DCC (0.089g, 0.43 mmol) and the mixture stirred at room temperature for 1 h. Afterthis time a thick granular precipitate had formed. 3-Aminoquinuclidinedihydrochloride (0.086 g, 0.43 mmol) and DMAP (0.010 g, 0.08 mmol) werethen added to the reaction followed by the dropwise addition oftriethylamine (0.101 g, 1.00 mmol) over 15 min. The reaction was thenstirred at room temperature overnight. Subsequent concentration of thereaction mixture and purification of the resulting solid residue bycolumn chromatography afforded 0.100 g (70% yield) ofN-(1-azabicyclo[2.2.2]oct-3-yl)-2-(4-fluorophenyl)benzoxazole-7-carboxamideas a white solid: mp 185-187° C.; ¹H NMR (500 MHz, DMSO-d₆) δ 8.46 (d,J=6.7 Hz, 1H), 8.24 (m, 2H), 7.95 (m, 1H), 7.70 (m, 1H), 7.51 (m, 3H),4.06 (m, 1H), 3.21 (m, 1H), 2.92 (m, 1H), 2.74 (m, 4H), 1.96 (m, 2H),1.64 (m, 2H), 1.44 (m, 1H); MS (ESI) m/z 366 [M+H]⁺.

Example 28 Preparation ofN-(9-Methyl-9-azabicyclo[3.3.1]non-3-yl)-2-(4-fluorophenyl)benzoxazole-7-carboxamide

N-(9-Methyl-9-azabicyclo[3.3.1]non-3-yl)-2-(4-fluorophenyl)benzoxazole-7-carboxamidewas prepared from 2-(4-fluorophenyl)benzoxazole-7-carboxylic acid and3-amino-9-methyl-9-azabicyclo[3.3.1]nonane dihydrochloride using themethod outlined in Step C of Example 14. This compound was obtained in15% yield as an off-white solid: mp 229-231° C.; ¹H NMR (500 MHz,DMSO-d₆) δ 8.26 (m, 2H), 8.20 (d, J=8.3 Hz, 1H), 7.94 (dd, J=1.0, 7.9Hz, 1H), 7.71 (dd, J=1.0, 7.6 Hz, 1H), 7.50 (m, 3H), 4.39 (m, 1H), 3.02(m, 2H), 2.43 (s, 3H), 2.32 (m, 2H), 2.08 (m, 1H), 1.93 (m, 2H), 1.48(m, 3H), 0.96 (m, 2H); MS (ESI) m/z 394 [M+H]⁺.

Example 29 Preparation ofN-(1-Azabicyclo[2.2.2]oct-3-yl)-2-(4-methoxyphenyl)benzoxazole-7-carboxamide

Step A: Methyl 2-(4-methoxyphenyl)benzoxazole-7-carboxylate was preparedfrom methyl 3-aminosalicylate and 4-methoxybenzoyl chloride as describedin Step A of Example 1. The crude material was suspended in thionylchloride (15 mL) and the mixture heated to reflux overnight. After thistime the reaction was cooled and concentrated to a dark oil. This oilwas treated with methanol and the solution stirred at room temperaturefor 1 h. Subsequent concentration afforded a dark brown solid which waspurified by column chromatography to afford a 24% yield of methyl2-(4-methoxyphenyl)benzoxazole-7-carboxylate as a yellow solid: ¹H NMR(500 MHz, DMSO-d₆) δ 8.19 (d, J=8.7 Hz, 2H), 8.04 (d, J=7.8 Hz, 1H),7.91 (d, J=7.8 Hz, 1H), 7.51 (t, J=7.8 Hz, 1H), 7.20 (d, J=8.7 Hz, 2H),3.99 (s, 3H); 3.88 (s, 3H); MS (ESI) m/z 284 [M+H]⁺.

Step B: Methyl 2-(4-methoxyphenyl)benzoxazole-7-carboxylate washydrolyzed to 2-(4-methoxyphenyl)benzoxazole-7-carboxylic acid usinglithium hydroxide as described in Step B of Example 14. This materialwas obtained in 65% yield as an off-white solid ¹H NMR (500 MHz,DMSO-d₆) δ 8.15 (d, J=8.7 Hz, 2H), 8.01 (d, J=7.8 Hz, 1H), 7.88 (d,J=7.8 Hz, 1H), 7.49 (t, J=7.8 Hz, 1H), 7.20 (d, J=8.7 Hz, 2H), 3.99 (s,3H); 3.83 (s, 3H); MS (ESI) m/z 270 [M+H]⁺.

Step C:N-(1-Azabicyclo[2.2.2]oct-3-yl)-2-(4-methoxyphenyl)benzoxazole-7-carboxamidewas prepared from 2-(4-methoxyphenyl)benzoxazole-7-carboxylic acid and3-aminoquinuclidine dihydrochloride using the method outlined in Step Cof Example 14. This compound was obtained in 24% yield as a white solid:mp 166-167° C.; ¹H NMR (500 MHz, CD₃OD) δ 8.20 (dd, J=7.0, 2.0 Hz, 2H),7.86 (d, J=7.9 Hz, 1H), 7.84 (d, J=7.9 Hz, 1H), 7.49 (t, J=7.9 Hz, 1H),7.14 (dd, J=1.9, 7.0 Hz, 2H), 4.26 (m, 1H), 3.91 (s, 3H), 3.42 (m, 1H),3.02 (m, 1H), 2.92 (m, 3H), 2.83 (m, 1H), 2.16 (d, J=3.1 Hz, 1H), 2.07(m, 1H), 1.84 (m, 2H), 1.68 (m, 1H); MS (ESI) m/z 378 [M+H]⁺.

Example 30 Preparation ofN-(9-Methyl-9-azabicyclo[3.3.1]non-3-yl)-2-(4-methoxyphenyl)benzoxazole-7-carboxamide

N-(9-Methyl-9-azabicyclo[3.3.1]non-3-yl)-2-(4-methoxyphenyl)benzoxazole-7-carboxamidewas prepared from 2-(4-methoxyphenyl)benzoxazole-7-carboxylic acid and3-amino-9-methyl-9-azabicyclo[3.3.1]nonane dihydrochloride using themethod outlined in Step C of Example 14. This compound was obtained in36% yield as a off-white solid: mp 160-162° C.; ¹H NMR (500 MHz, CD₃OD)δ 8.22 (dt, J=9.7, 2.8 Hz, 2H), 7.82 (dd, J=7.9, 1.0 Hz, 1H), 7.72 (dd,J=7.7, 1.0 Hz, 1H), 7.46 (t, J=7.8 Hz, 1H), 7.14 (dt, J=9.7, 2.8 Hz,2H), 4.61 (m, 1H), 3.90 (s, 3H), 3.16 (m, 2H), 2.59 (m, 2H), 2.55 (s,3H), 2.14 (m, 1H), 2.08 (m, 2H), 1.61 (m, 3H), 1.99 (m, 2H); MS (ESI)m/z 406 [M+H]⁺.

Example 31 Preparation ofN-(1-Azabicyclo[2.2.2]oct-3-yl)-2-(4-chlorophenyl)benzoxazole-7-carboxamide

Step A: Methyl 2-(4-chlorophenyl)benzoxazole-7-carboxylate was preparedfrom 3-hydroxysalicylic acid and 4-chlorobenzoyl chloride using themethod described in Step A of Example 14 in 45% overall yield. Thismaterial was obtained as a white solid: ¹H NMR (300 MHz, CDCl₃) δ 8.25(dd, J=6.6, 1.8 Hz, 2H), 8.04 (d, J=8.1 Hz, 1H), 7.78 (d, J=8.1 Hz, 1H),7.52 (d, J=8.7 Hz, 2H), 7.43 (t, J=7.8 Hz, 1H), 4.06 (s, 3H); MS (ESI)m/z 288 [M+H]⁺.

Step B: Methyl 2-(4-chlorophenyl)benzoxazole-7-carboxylate was convertedto 2-(4-chlorophenyl)benzoxazole-7-carboxylic acid by lithium hydroxidemediated hydrolysis using the procedure described in Step B of Example14. This material was obtained in 84% yield as a white solid: ¹H NMR(500 MHz, DMSO-d₆) δ 13.49 (br s, 1H), 8.20 (d, J=8.5 Hz, 2H), 8.07 (d,J=8.0 Hz, 1H), 7.95 (d, J=7.5 Hz, 1H), 7.72 (d, J=8.5 Hz, 2H), 7.53 (t,J=7.5 Hz, 1H); MS (ESI) m/z 274 [M+H]⁺.

Step C:N-(1-Azabicyclo[2.2.2]oct-3-yl)-2-(4-chlorophenyl)benzoxazole-7-carboxamidewas prepared from 2-(4-chlorophenyl)benzoxazole-7-carboxylic acid and3-aminoquinuclidine dihydrochloride using the method outlined in Step Cof Example 14. This compound was obtained in 55% yield as a off-whitesolid: mp 181-183° C.; ¹H NMR (500 MHz, CDCl₃) δ 8.14 (d, J=8.6 Hz, 2H),8.11 (dd, J=1.0, 11.1 Hz, 2H), 7.92 (dd, J=1.0, 7.9 Hz, 1H), 7.56 (d,J=8.6 Hz, 2H), 7.50 (t, J=7.8 Hz, 1H), 7.32 (d, J=7.1 Hz, 1H), 4.31 (m,1H), 3.57 (dd, J=9.4, 14.4 Hz, 1H), 3.01 (t, J=7.9 Hz, 2H), 2.92 (m,2H), 2.74 (m, 1H), 2.17 (m, 1H), 1.91 (m, 1H), 1.78 (m, 2H), 1.63 (m,4H); MS (ESI) m/z 382 [M+H]⁺.

Example 32 Preparation ofN-(9-Methyl-9-azabicyclo[3.3.1]non-3-yl)-2-(4-chlorophenyl)benzoxazole-7-carboxamide

N-(9-Methyl-9-azabicyclo[3.3.1]non-3-yl)-2-(4-chlorophenyl)benzoxazole-7-carboxamidewas prepared from 2-(4-chlorophenyl)benzoxazole-7-carboxylic acid and3-amino-9-methyl-9-azabicyclo[3.3.1]nonane dihydrochloride using themethod outlined in Step C of Example 14. This compound was obtained in43% yield as an off-white solid: mp 193-196° C.; ¹H NMR (500 MHz,DMSO-d₆) δ 8.14 (d, J=8.4 Hz, 2H), 8.06 (d, J=7.7 Hz, 1H), 7.88 (d,J=7.7 Hz, 1H), 7.55 (d, J=8.4 Hz, 2H), 7.46 (t, J=7.8 Hz, 1H); 6.88 (d,J=6.6 Hz, 1H), 4.62 (m, 1H), 3.19 (d, J=10.0 Hz, 2H), 2.84-2.60 (m, 2H),2.56 (s, 3H), 2.08 (m, 3H), 1.60 (m, 1H), 1.50 (t, J=11.4 Hz, 2H),1.30-1.15 (m, 2H); MS (ESI) m/z 410 [M+H]⁺.

Example 35 Preparation ofN-(1-Azabicyclo[2.2.2]oct-3-yl)-2-(3-methoxyphenyl)benzoxazole-4-carboxamide

Step A: To a suspension of 2-amino-3-hydroxybenzoic acid (100 mg, 0.65mmol) in dichloromethane (15 mL) was added pyridine (0.32 ml, 3.92 mmol)followed by m-anisoyl chloride (0.35 mL, 2.61 mmol) at room temperature.The resulting reaction mixture was stirred at room temperature for 15min and DMAP (8 mg, 0.07 mmol) was added, then the reaction mixture wasstirred at room temperature overnight. The reaction was quenched withaqueous 1 N HCl (30 mL) until the solution reached pH 1. The solutionwas stirred for 30 min. The aqueous layer was extracted with ethylacetate. The organic layers were washed with brine, dried over Na₂SO₄,filtered and concentrated. The product was dissolved in toluene (10 mL)and the solution treated with p-toluenesulfonic acid monohydrate (274mg, 1.44 mmol). The reaction mixture was then heated to refluxovernight. The reaction was cooled down to room temperature, poured intowater and extracted with ethyl acetate. The organic layer was separatedthen washed with water, brine, dried over Na₂SO₄, filtered andconcentrated to a yellow solid. The crude product was purified by columnchromatography (silica gel, 9:1 to 2:1, ethyl acetate/methanol) toafford the desired product (61 mg, 24%): MS (ESI+) m/z 270 (M+H).

Step B: A mixture of 2-(2-methoxyphenyl)benzoxazole-4-carboxylic acidfrom Step A (59 mg, 0.22 mmol), 3-aminoquinuclidine dihydrochloride (51mg, 0.26 mmol), 1-ethyl-3-(3-dimethylaminopropyl)carbodiimidehydrochloride (84 mg, 0.44 mmol) and 1-hydroxybenzotriazole (59 mg, 0.44mmol) in DMF (10 mL) was stirred for 10 min at room temperature, thenDIPEA (0.14 mL, 0.88 mmol) was added. The resulting reaction mixture wasstirred at room temperature overnight. The mixture was diluted withethyl acetate (20 mL), and then washed with a saturated solution ofsodium bicarbonate. The aqueous layer was further extracted with ethylacetate (2×50 mL). The combined organics were dried (Na₂SO₄), filteredand concentrated. The crude material was purified by columnchromatography (silica gel, 90:9:1 ethyl acetate/methanol/concentratedammonium hydroxide) to affordN-(1-azabicyclo[2.2.2]oct-3-yl)-2-(3-methoxyphenyl)benzoxazole-4-carboxamide(38 mg, 46%) as a white solid: ¹H NMR (500 MHz, CDCl₃) δ 9.60 (d, J=7.5Hz, 1H), 8.20 (dd, J=7.5, 1.0 Hz, 1H), 7.86-7.82 (m, 1H), 7.78-7.75 (m,1H), 7.72 (dd, J=8.0, 1.0 Hz, 2H), 7.48 (t, J=16.0 Hz, 2H), 7.15 (dd,J=8.5, 2.5 Hz, 1H), 4.36-4.28 (m, 1H), 3.56-3.48 (m, 1H), 3.10 (s, 3H),3.15-2.98 (m, 2H), 2.96-2.87 (m, 2H), 2.86-2.79 (m, 1H), 2.20-2.05 (m,2H), 1.80-1.60 (m, 2H); MS (ESI+) m/z 378 (M+H); HPLC >99% (AUC),t_(R)=12.48 min.

Example 36 Preparation of(S)-N-(1-Azabicyclo[2.2.2]oct-3-yl)-2-(2-hydroxyphenyl)benzoxazole-4-carboxamideHydrochloride

(S)-Enantiomer

Step A: A mixture of 2-(2-methoxyphenyl)benzoxazole-4-carboxylic acid(160 mg, 0.59 mmol) and 48% hydrobromic acid (10 mL) was heated toreflux overnight. The reaction mixture was cooled to room temperatureand the solid was filtered and washed with diethyl ether to afford thedesired product (154 mg, 81%) as a brown solid: ¹H NMR (500 MHz,DMSO-d₆) δ 13.08 (br s, 1H), 8.06 (dd, J=7.8, 1.8 Hz, 1H), 8.04 (dd,J=8.0, 1.1 Hz, 1H), 7.91 (dd, J=7.8, 1.0 Hz, 1H), 7.67-7.61 (m, 2H),7.51 (t, J=7.9 Hz, 1H), 7.32-7.28 (m, 1H), 7.19-7.14 (m, 1H); MS (ESI+)m/z 256 (M+H).

Step B: A mixture of 2-(2-hydroxyphenyl)benzoxazole-4-carboxylic acid(50 mg, 0.2 mmol), 1-ethyl-3-(3-dimethylaminopropyl)carbodiimidehydrochloride (75 mg, 0.4 mmol), 1-hydroxybenzotriazole (57 mg, 0.4mmol) and (S)-(−)-3-aminoquinuclidine dihydrochloride (39 mg, 0.2 mmol)in DMF (5 mL) was stirred at room temperature for 10 min, thentriethylamine (0.08 mL, 0.6 mmol) was added. The resulting reactionmixture was stirred at room temperature for 12 h. The reaction mixturewas diluted with ethyl acetate (50 mL), and then treated with asaturated solution of sodium bicarbonate. The organic layer was isolatedand the aqueous layer was further extracted with ethyl acetate (2×50mL). The combined organics were washed with water (2×25 mL), brine (2×25mL), dried (Na₂SO₄), filtered and concentrated. The crude material waspurified by semi-preparative HPLC to afford the desired product (49 mg,68%) as a light yellow solid: ¹H NMR (500 MHz, CDCl₃) δ 10.43 (s, 1H),8.37 (d, J=6.7 Hz, 1H), 8.22 (dd, J=7.8, 1.0 Hz, 1H), 8.10 (dd, J=7.9,1.6 Hz, 1H), 7.77 (dd, J=8.1, 0.9 Hz, 1H), 7.55-7.50 (m, 2H), 7.16 (dd,J=8.6, 0.6 Hz, 1H), 7.08 (t, J=7.0 Hz, 1H), 4.40-4.30 (m, 1H), 3.63-3.55(m, 1H), 3.22-3.20 (m, 1H), 3.07-2.90 (m, 3H), 2.87-2.80 (m, 1H),2.22-2.17 (m, 1H), 2.02-1.92 (m, 1H), 1.85-1.78 (m, 2H), 1.73-1.65 (m,1H); MS (ESI+) m/z 364 (M+H).

Step C: To a solution of(S)-N-(1-azabicyclo[2.2.2]oct-3-yl)-2-(2-hydroxyphenyl)benzoxazole-4-carboxamide(46 mg, 0.12 mmol) in methanol (1.0 mL) was added a solution of HCl indiethyl ether (1 N, 0.13 mL, 0.13 mmol) at room temperature slowly. Thereaction mixture was diluted with diethyl ether. The resulting solid wasfiltered and washed with diethyl ether to afford(S)-N-(1-azabicyclo[2.2.2]oct-3-yl)-2-(2-hydroxyphenyl)benzoxazole-4-carboxamidehydrochloride (36 mg, 72%) as a white solid: ¹H NMR (500 MHz, DMSO-d₆) δ10.93 (s, 1H), 10.07 (br s, 1H), 9.29 (d, J=6.5 Hz, 1H), 8.08 (dd,J=7.8, 1.6 Hz, 1H), 8.03 (dd, J=8.1, 0.9 Hz, 1H), 7.90 (dd, J=7.7, 0.8Hz, 1H), 7.59-7.51 (m, 2H), 7.19 (d, J=8.3 Hz, 1H), 7.12-7.06 (m, 1H),4.50-4.42 (m, 1H), 3.80-3.70 (m, 1H), 3.40-3.20 (m, 5H), 2.35-2.25 (m,2H), 2.00-1.95 (m, 2H), 1.95-1.85 (m, 1H); MS (ESI+) m/z 364 (M+H);HPLC >99% (AUC), t_(R)=11.64 min.

Example 37 Preparation ofN-(9-Methyl-9-azabicyclo[3.3.1]non-3-yl)-2-(2-hydroxyphenyl)benzoxazole-4-carboxamideHydrochloride

Step A: A mixture of 2-(2-hydroxyphenyl)benzoxazole-4-carboxylic acid(96 mg, 0.37 mmol), 1-ethyl-3-(3-dimethylaminopropyl)carbodiimidehydrochloride (143 mg, 0.75 mmol), 1-hydroxybenzotriazole (102 mg, 0.75mmol) and 3-amino-9-methyl-9-azabicyclo[3.3.1]nonane dihydrochloride (85mg, 0.37 mmol) in DMF (5 mL) was stirred at room temperature for 10 min,then triethylamine (0.15 mL, 1.12 mmol) was added. The resultingreaction mixture was stirred at room temperature overnight. The mixturewas diluted with dichloromethane and then washed with a saturatedsolution of sodium bicarbonate. The aqueous layer was further extractedwith dichloromethane (2×50 mL). The combined organic layers were washedwith water (2×50 mL) and brine (2×50 mL), dried (Na₂SO₄), filtered andconcentrated. The crude material was purified by column chromatography(silica gel, 90:9:1 dichloromethane/methanol/concentrated ammoniumhydroxide) and recrystallization from acetonitrile to afford the desiredproduct (70 mg, 48%) as a white solid: ¹H NMR (500 MHz, CDCl₃) δ 10.54(s, 1H), 8.21 (dd, J=7.8, 1.1 Hz, 1H), 8.09 (dd, J=8.1, 1.6 Hz, 1H),7.80-7.77 (m, 1H), 7.75 (dd, J=8.1, 0.9 Hz, 1H), 7.57-7.50 (m, 2H), 7.17(dd, J=8.6, 0.6 Hz, 1H), 7.10-7.05 (m, 1H), 4.70-4.60 (m, 1H), 3.25-3.15(m, 2H), 2.73-2.69 (m, 2H), 2.56 (s, 3H), 2.15-1.95 (m, 2H), 1.65-1.45(m, 4H), 1.25-1.10 (m, 2H); MS (ESI+) m/z 392 (M+H).

Step B: To a solution ofN-(9-methyl-9-azabicyclo[3.3.1]non-3-yl)-2-(2-hydroxyphenyl)benzoxazole-4-carboxamide(66 mg, 0.17 mmol) in methanol (1.0 mL) was added a solution of HCl indiethyl ether (1 N, 0.18 mL, 0.18 mmol) at room temperature slowly. Thereaction mixture was diluted with diethyl ether. The resulting solid wasfiltered and washed with diethyl ether to affordN-(9-methyl-9-azabicyclo[3.3.1]non-3-yl)-2-(2-hydroxyphenyl)benzoxazole-4-carboxamidehydrochloride (39 mg, 54%) as a white solid: ¹H NMR (500 MHz, CDCl₃) δ12.30 (br s, 0.5H), 12.01 (br s, 0.5H), 8.30-8.10 (m, 2H), 7.90-7.75 (m,1H), 7.58-7.50 (m, 2H), 7.18-7.12 (m, 2H), 4.95-4.85 (m, 0.5H),4.70-4.60 (m, 0.5H), 3.70-3.55 (m, 2H), 3.25-3.15 (m, 1H), 3.00-2.75 (m,5H), 2.50-2.00 (m, 5H), 1.90-1.50 (m, 4H); MS (ESI+) m/z 392 (M+H); HPLC96.7% (AUC), t_(R)=12.44 min.

Example 38 Preparation ofN-(9-Methyl-9-azabicyclo[3.3.1]non-3-yl)-2-(2-bromophenyl)benzoxazole-4-carboxamideHydrochloride

Step A: To a suspension of 2-amino-3-hydroxybenzoic acid hydrobromide(2.0 g, 8.5 mmol) in dichloromethane (50 mL) was added triethyamine(4.77 mL, 34.2 mmol) followed by 2-bromobenzoyl chloride (1.12 mL, 8.54mmol) at room temperature. The resulting reaction mixture was stirred atroom temperature overnight. The reaction was quenched with aqueous 2 NHCl (50 mL). The reaction mixture was extracted with dichloromethane.The combined organic layers were dried over Na₂SO₄, filtered andconcentrated to a brown solid. The crude was dissolved in toluene (10mL) and the solution was treated with p-toluenesulfonic acid monohydrate(2.45 g, 12.8 mmol). The resulting reaction mixture was then heated at90° C. under nitrogen for 4 h. The reaction was cooled to roomtemperature, poured into water and extracted with dichloromethane (400mL). The organic layer was separated, washed with water and brine, driedover Na₂SO₄, filtered and concentrated to a brown solid. The crudeproduct was purified by recrystallization from methanol to afford thedesired product (1.51 g, 55%) as a brown solid: ¹H NMR (500 MHz,DMSO-d₆) δ 13.08 (br s, 1H), 8.06 (dd, J=7.8, 1.8 Hz, 1H), 8.04 (dd,J=8.0, 1.1 Hz, 1H), 7.91 (dd, J=7.8, 1.0 Hz, 1H), 7.67-7.61 (m, 1H),7.51 (t, J=7.9 Hz, 1H), 7.32-7.28 (m, 1H), 7.19-7.14 (m, 1H); MS (ESI+)m/z 319 (M+H).

Step B: A mixture of the 2-(2-bromophenyl)benzoxazole-4-carboxylic acid(1.00 g, 3.14 mmol), 3-amino-9-methyl-9-azabicyclo[3.3.1]nonanedihydrochloride (1.07 g, 4.72 mmol),1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (1.20 g,6.28 mmol), 1-hydroxybenzotriazole (0.85 g, 6.3 mmol) and DMF (20 mL)was stirred under nitrogen at room temperature for 10 min, and thentriethylamine (1.75 mL, 12.6 mmol) was added. The resulting reactionmixture was stirred at room temperature overnight, then quenched with asaturated solution of sodium bicarbonate and extracted with methylenechloride. The combined organic layers were washed with brine, dried(Na₂SO₄), filtered and concentrated. The crude material was purified bycolumn chromatography (silica gel, 90:9:1dichloromethane/methanol/concentrated ammonium hydroxide) to afford thedesired amide (910 mg, 64%) as an off-white solid: ¹H NMR (500 MHz,CDCl₃) δ 9.73 (d, J=7.2 Hz, 1H), 8.25 (dd, J=8.1, 1.8 Hz, 1H), 8.21 (dd,J=7.8, 1.0 Hz, 1H), 7.85 (dd, J=9.2, 1.0 Hz, 1H), 7.73 (d, J=8.2 Hz,1H), 7.55-7.50 (m, 2H), 7.45-7.40 (m, 1H), 4.67-4.53 (m, 1H), 3.23-3.15(m, 2H), 2.72-2.50 (m, 5H), 2.15-1.95 (m, 3H), 1.62-1.53 (m, 3H),1.21-1.15 (m, 2H); MS (ESI+) m/z 455 (M+H).

Step C: To a solution of the amide from Step B (50 mg, 0.11 mmol) indichloromethane (1.0 mL) was added a solution of HCl in diethyl ether (1N, 0.11 mL, 0.11 mmol) at 0° C. slowly. The reaction mixture was dilutedwith diethyl ether. The resulting solid was filtered and washed withdiethyl ether to affordN-(9-methyl-9-azabicyclo[3.3.1]non-3-yl)-2-(2-bromophenyl)benzoxazole-4-carboxamidehydrochloride (56 mg, 96%) as a white solid: ¹H NMR (500 MHz, CDCl₃) δ12.15 (br s, 0.5H), 11.78 (br s, 0.5H), 9.48 (d, J=5.8 Hz, 1H), 8.22(dd, J=7.8, 0.8 Hz, 0.5H), 8.18 (dd, J=7.8, 0.8 Hz, 0.5H), 8.15-8.12 (m,1H), 7.86-7.76 (m, 2H), 7.61-7.51 (m, 2H), 7.50-7.41 (m, 1H), 4.93-4.84(m, 0.5H), 4.70-4.60 (m, 0.5H), 3.63-3.55 (m, 2H), 2.98-2.90 (m, 3H),2.83-2.75 (m, 2H), 2.55-2.45 (m, 1H), 2.20-2.05 (m, 2H), 1.95-1.90 (m,2H), 1.80-1.70 (m, 3H); MS (ESI+) m/z 455 (M+H); HPLC >99% (AUC),t_(R)=12.72 min.

Example 39 Preparation ofN-(9-Methyl-9-azabicyclo[3.3.1]non-3-yl)-2-(2-aminophenyl)benzoxazole-4-carboxamideDihydrochloride

Step A: A dry flask was charged withN-(9-methyl-9-azabicyclo[3.3.1]non-3-yl)-2-(2-bromophenyl)benzoxazole-4-carboxamide(300 mg, 0.7 mmol), tert-butyl carbamate (115 mg, 0.990 mmol), Pd(OAc)₂(15 mg, 0.07 mmol), xantphos (57 mg, 0.10 mmol) and cesium carbonate(300 mg, 0.92 mmol) and 1,4-dioxane (5 mL). The mixture was degassedwith argon. The resulting reaction mixture was heated at 100° C. for 12h. The reaction mixture was cooled to room temperature, and then dilutedwith methylene chloride and water. The reaction mixture was extractedwith methylene chloride (2×50 mL). The combined organic layers werewashed with brine, dried (Na₂SO₄) and concentrated under reducedpressure. The crude material was purified by column chromatography(silica gel, 90:9:1 dichloromethane/methanol/concentrated ammoniumhydroxide) to afford the desired carbamate (229 mg, 71%) as a lightyellow solid: ¹H NMR (500 MHz, CDCl₃) δ 9.85 (br s, 1H), 8.43 (d, J=8.5Hz, 1H), 8.22 (dd, J=8.7, 0.9 Hz, 1H), 8.17 (d, J=7.3 Hz, 1H), 8.12 (dd,J=7.9, 1.5 Hz, 1H), 7.73 (dd, J=8.1, 1.0 Hz, 1H), 7.58-7.54 (m, 1H),7.50 (t, J=7.9 Hz, 1H), 7.21-7.15 (m, 1H), 4.57-4.52 (m, 1H), 3.12-3.08(m, 1H), 2.62-2.58 (m, 2H), 2.52 (s, 3H), 2.15-1.95 (m, 3H), 1.65-1.50(m, 13H), 1.10-1.05 (m, 2H); MS (ESI+) m/z 491 (M+H).

Step B: To a solution of the carbamate from Step A (225 mg, 0.460 mmol)in methylene chloride (1 mL) was added HCl in 1,4-dioxane (4.0 N, 0.34mL, 1.37 mmol) at 0° C. The reaction mixture was allowed to warn to roomtemperature and stirred for 4 h. The resulting precipitate was isolatedby filtration, washed with diethyl ether and dried under high vacuum toaffordN-(9-methyl-9-azabicyclo[3.3.1]non-3-yl)-2-(2-aminophenyl)benzoxazole-4-carboxamidedihydrochloride (53 mg, 25%) as an off-white solid: ¹H NMR (500 MHz,DMSO-d₆) δ 10.30 (br s, 0.2H), 9.44 (br s, 0.8H), 8.71 (d, J=5.4 Hz,0.2H), 8.57 (d, J=7.6 Hz, 0.8H), 8.00-7.94 (m, 2H), 7.90-7.82 (m, 1H),7.55-7.47 (m, 1H), 7.38-7.30 (m, 1H), 7.00-6.93 (m, 1H), 6.75-6.62 (m,1H), 4.75-4.35 (m, 4H), 3.70-3.65 (m, 1.6H), 3.60-3.55 (m, 0.4H),2.90-2.80 (m, 3H), 2.75-2.60 (m, 3H), 2.20-2.05 (m, 3H), 1.90-1.80 (m,2H), 1.60-1.50 (m, 2H); MS (ESI+) m/z 391 (M+H); HPLC >99% (AUC),t_(R)=12.28 min.

Example 40 Preparation ofN-(9-Methyl-9-azabicyclo[3.3.1]non-3-yl)-2-(biphenyl-2-yl)benzoxazole-4-carboxamideHydrochloride

Step A: A mixture ofN-(9-methyl-9-azabicyclo[3.3.1]non-3-yl)-2-(2-bromophenyl)benzoxazole-4-carboxamide(100 mg, 0.22 mmol), phenylboronic acid (40 mg, 0.33 mmol), and aqueous2 M Na₂CO₃ (1.5 mL) in toluene (4 mL) was degassed with argon for 15min. To the mixture was added Pd(PPh₃)₄ (25 mg, 0.022 mmol), and theresulting reaction mixture was heated at 80° C. for 12 h. The reactionmixture was cooled to room temperature, filtered through a microfilterand the filtrate was concentrated to give an off-white solid. The crudematerial was purified by preparative TLC (90:9:1 methylenechloride/methanol/concentrated ammonium hydroxide) to afford the desiredamide (94 mg, 94%) as a white solid: ¹H NMR (500 MHz, CDCl₃) δ 8.56 (brs, 1H), 8.16 (d, J=7.6 Hz, 1H), 8.09 (d, J=7.6 Hz, 1H), 7.65-7.61 (m,1H), 7.58-7.47 (m, 3H), 7.39 (t, J=8.0 Hz, 1H), 7.38-7.28 (m, 5H),4.52-4.43 (m, 1H), 3.20-3.05 (m, 2H), 2.65-2.40 (m, 5H), 2.15-1.95 (m,3H), 1.62-1.53 (m, 2H), 1.21-1.15 (m, 2H); MS (ESI+) m/z 452 (M+H).

Step B: To a solution of the amide from Step A (82 mg, 0.18 mmol) indichloromethane (1.0 mL) was added a solution of HCl in diethyl ether (1N, 0.20 mL, 0.20 mmol) at 0° C. slowly. The reaction mixture was dilutedwith diethyl ether. The resulting solid was filtered and washed withdiethyl ether to affordN-(9-methyl-9-azabicyclo[3.3.1]non-3-yl)-2-(biphenyl-2-yl)benzoxazole-4-carboxamidehydrochloride (56 mg, 96%) as a white solid: ¹H NMR (500 MHz, DMSO-d₆) δ9.83 (br s, 0.2H), 9.17 (br s, 0.8H), 8.95 (d, J=5.6 Hz, 0.2H), 8.43 (d,J=5.6 Hz, 0.8H), 8.20-8.10 (m, 1H), 7.98-7.92 (m, 1H), 7.85 (d, J=8.1Hz, 1H), 7.80-7.75 (m, 1H), 7.65-7.60 (m, 1H), 7.55-7.50 (m, 1H),7.40-7.35 (m, 5H), 4.55-4.47 (m, 0.8H), 4.35-4.25 (m, 0.2H), 3.70-3.65(m, 1.6H), 3.60-3.55 (m, 0.4H), 2.90-2.80 (m, 3H), 2.70-2.60 (m, 1H),2.47-2.40 (m, 2H), 2.20-2.00 (m, 3H), 1.90-1.80 (m, 3H), 1.60-1.47 (m,2H); MS (ESI+) m/z 452 (M+H); HPLC >99% (AUC), t_(R)=12.97 min.

Example 41 Preparation ofN-(9-Methyl-9-azabicyclo[3.3.1]non-3-yl)-2-(2-pyridine-4-yl)phenylbenzoxazole-4-carboxamideDihydrochloride

Step A: A mixture ofN-(9-methyl-9-azabicyclo[3.3.1]non-3-yl)-2-(2-bromophenyl)benzoxazole-4-carboxamide(100 mg, 0.22 mmol), 4-pyridine boronic acid (40 mg, 0.33 mmol), andaqueous 2 M Na₂CO₃ (1.5 mL) in toluene (4 mL) was degassed with argonfor 15 min. To the mixture was added Pd(PPh₃)₄ (25 mg, 0.022 mmol), andthe resulting reaction mixture was heated at 80° C. for 12 h. Thereaction mixture was cooled to room temperature, filtered through amicrofilter and the filtrate was concentrated to give an off-whitesolid. The crude material was purified by preparative TLC (90:9:1methylene chloride/methanol/concentrated ammonium hydroxide) to affordthe desired amide (63 mg, 63%) as an off-white solid: ¹H NMR (500 MHz,CDCl₃) δ 8.63 (br s, 2H), 8.16 (d, J=7.6 Hz, 2H), 7.72-7.61 (m, 2H),7.58-7.50 (m, 2H), 7.39 (t, J=8.0 Hz, 1H), 7.38-7.28 (m, 3H), 4.52-4.43(m, 1H), 3.20-3.05 (m, 2H), 2.70-2.40 (m, 5H), 2.15-1.95 (m, 3H),1.62-1.53 (m, 4H), 1.21-1.15 (m, 2H); MS (ESI+) m/z 453 (M+H).

Step B: To a solution of the amide from Step A (63 mg, 0.14 mmol) inmethanol (1.0 mL) was added a solution of HCl in diethyl ether (1 N,0.42 mL, 0.42 mmol) at 0° C. slowly. The reaction mixture was dilutedwith diethyl ether. The resulting solid was filtered and washed withdiethyl ether to affordN-(9-methyl-9-azabicyclo[3.3.1]non-3-yl)-2-(2-pyridine-4-yl)phenylbenzoxazole-4-carboxamidedihydrochloride (53 mg, 72%) as a white solid: ¹H NMR (500 MHz, DMSO-d₆)δ 10.44 (br s, 0.2H), 9.63 (br s, 0.8H), 8.85-8.81 (m, 2H), 8.32-8.05(m, 2H), 7.98-7.70 (m, 8H), 7.56 (d, J=8.1 Hz, 1H), 7.40-7.36 (m, 1H),4.55-4.47 (m, 0.8H), 4.35-4.25 (m, 0.2H), 3.75-3.65 (m, 1.6H), 3.63-3.57(m, 0.4H), 2.90-2.80 (m, 3H), 2.47-2.40 (m, 2H), 2.22-2.00 (m, 3H),1.80-1.47 (m, 5H); MS (ESI+) m/z 453 (M+H); HPLC >99% (AUC), t_(R)=11.91min

Example 42 Preparation ofN-(1-Azabicyclo[2.2.2]oct-3-yl)-2-p-tolylbenzoxazole-4-carboxamide

Step A: To a suspension of 2-amino-3-hydroxy benzoic acid (100 mg, 0.65mmol) in dichloromethane (15 mL) was added pyridine (0.32 mL, 3.92 mmol)followed by 4-methylbenzoyl chloride (0.34 mL, 2.61 mmol) at roomtemperature. The resulting reaction mixture was stirred at roomtemperature for 15 min then DMAP (8 mg, 0.07 mmol) was added and thereaction mixture was stirred at room temperature overnight. The reactionwas quenched with aqueous 1 N HCl (30 mL) until the solution reachedpH 1. The solution was stirred for 30 min. The aqueous layer wasextracted with ethyl acetate. The organic layers were washed with brine,dried over Na₂SO₄, filtered and concentrated to give an orange solid.The product was directly re-dissolved in toluene (10 mL) and thesolution treated with p-toluenesulfonic acid monohydrate (311 mg, 1.63mmol). The reaction mixture was then heated to reflux overnight. Thereaction was cooled down to room temperature, poured into water andextracted with ethyl acetate. The organic layer was separated thenwashed with water, brine, dried over Na₂SO₄, filtered and concentratedto give an orange solid. The crude product was purified by columnchromatography (silica gel, 9:1 to 2:1, ethyl acetate/methanol) toafford the desired product (128 mg, 46%) as a pale orange solid: MS(ESI+) m/z 254 (M+H).

Step B: A mixture of 2-p-tolylbenzoxazole-4-carboxylic acid from Step A(62 mg, 0.24 mmol), 3-aminoquinuclidine dihydrochloride (58 mg, 0.29mmol), 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (94mg, 0.49 mmol) and 1-hydroxybenzotriazole (66 mg, 0.49 mmol) in DMF (5mL) was stirred for 10 min at room temperature, then DIPEA (0.16 mL,0.98 mmol) was added. The resulting reaction mixture was stirred at roomtemperature overnight. The mixture was diluted with ethyl acetate (20mL), and then washed with a saturated solution of sodium bicarbonate.The aqueous layer was further extracted with ethyl acetate (2×50 mL).The combined organics were dried (Na₂SO₄), filtered and concentrated.The crude material was purified by column chromatography (silica gel,90:9:1 ethyl acetate/methanol/concentrated ammonium hydroxide) to affordN-(1-azabicyclo[2.2.2]oct-3-yl)-2-p-tolylbenzoxazole-4-carboxamide (57mg, 66%) as a white solid: ¹H NMR (500 MHz, CDCl₃) δ 9.61 (d, J=7.0 Hz,1H), 8.18 (dd, J=8.0, 1.0 Hz, 1H), 8.13 (d, J=8.0 Hz, 2H), 7.70 (dd,J=8.5, 1.0 Hz, 1H), 7.45 (t, J=8.0 Hz, 1H), 7.37 (d, J=8.5 Hz, 2H),4.35-4.30 (m, 1H), 3.55-3.50 (m, 1H), 3.15-2.99 (m, 2H), 2.95-2.89 (m,2H), 2.88-2.81 (m, 1H), 2.48 (s, 3H), 2.19-2.15 (m, 1H), 2.13-2.05 (m,1H), 1.81-1.75 (m, 2H) 1.68-1.60 (m, 1H); MS (ESI+) m/z 362 (M+H); HPLC98.4% (AUC), t_(R)=12.90 min.

Example 43 Preparation ofN-(9-Methyl-9-azabicyclo[3.3.1]non-3-yl)-2-p-tolylbenzoxazole-4-carboxamide

A mixture of 2-p-tolylbenzoxazole-4-carboxylic acid (62 mg, 0.24 mmol),3-amino-9-methyl-9-azabicyclo[3.3.1]nonane dihydrochloride (66 mg, 0.29mmol), 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (94mg, 0.49 mmol) and 1-hydroxybenzotriazole (66 mg, 0.49 mmol) in DMF (5mL) was stirred for 10 min at room temperature, then DIPEA (0.16 mL,0.98 mmol) was added. The resulting reaction mixture was stirred at roomtemperature overnight. The mixture was diluted with ethyl acetate (20mL), and then washed with a saturated solution of sodium bicarbonate.The aqueous layer was further extracted with ethyl acetate (2×50 mL).The combined organics were dried (Na₂SO₄), filtered and concentrated.The crude material was purified by column chromatography (silica gel,90:9:1 ethyl acetate/methanol/concentrated ammonium hydroxide) to affordN-(9-methyl-9-azabicyclo[3.3.1]non-3-yl)-2-p-tolylbenzoxazole-4-carboxamide(25 mg, 27%) as a white solid: ¹H NMR (500 MHz, CDCl₃) δ 9.10 (d, J=7.0Hz, 1H), 8.20 (dd, J=7.5, 0.5 Hz, 1H), 8.14 (d, J=8.5 Hz, 2H), 7.68 (dd,J=8.0, 1.0 Hz, 1H), 7.45 (t, J=7.0 Hz, 1H), 7.39 (d, J=8.0 Hz, 2H),4.64-4.55 (m, 1H), 3.17-3.11 (m, 2H), 2.70-2.60 (m, 2H) 2.56 (s, 3H),2.48 (s, 3H), 2.08-1.98 (m, 2H), 1.75-1.50 (m, 3H), 1.25-1.17 (m, 3H);MS (ESI+) m/z 390 (M+H); HPLC >99% (AUC), t_(R)=13.37 min.

Example 44 Preparation ofN-(1-Azabicyclo[2.2.2]oct-3-yl)-2-(4-nitrophenyl)benzoxazole-4-carboxamide

Step A: To a suspension of 2-amino-3-hydroxybenzoic acid (300 mg, 1.96mmol) in dichloromethane (40 mL) was added pyridine (0.95 mL, 11.8 mmol)followed by 4-nitrobenzoyl chloride (1.45 g, 7.84 mmol) at roomtemperature. The resulting reaction mixture was stirred at roomtemperature for 15 min then DMAP (24 mg, 0.20 mmol) was added and thereaction mixture was stirred at room temperature overnight. The reactionwas quenched with aqueous 1 N HCl (30 mL) until the solution reachedpH 1. The solution was stirred for 30 min. The aqueous layer wasextracted with ethyl acetate. The organic layers were washed with brine,dried over Na₂SO₄, filtered and concentrated to give a yellow solid. Theproduct was directly re-dissolved in toluene (30 mL) and the solutiontreated with p-toluenesulfonic acid monohydrate (618 mg, 1.63 mmol). Thereaction mixture was then heated to reflux overnight. The reaction wascooled down to room temperature, poured into water and extracted withethyl acetate. The organic layer was separated then washed with water,brine, dried over Na₂SO₄, filtered and concentrated to give an orangesolid. The crude product was purified by column chromatography (silicagel, 9:1 to 2:1 ethyl acetate/methanol) to afford the desired product(628 mg, quantitative) as a pale orange solid: MS (ESI+) m/z 285 (M+H).

Step B: A mixture of 2-(4-nitrophenyl)benzoxazole-4-carboxylic acid fromStep A (311 mg, 1.09 mmol), 3-aminoquinuclidine dihydrochloride (261 mg,1.31 mmol), 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride(265 mg, 2.19 mmol) and 1-hydroxybenzotriazole (296 mg, 2.19 mmol) inDMF (5 mL) was stirred for 10 min at room temperature, then DIPEA (0.72mL, 4.38 mmol) was added. The resulting reaction mixture was stirred atroom temperature overnight. The mixture was diluted with ethyl acetate(20 mL), and then washed with a saturated solution of sodiumbicarbonate. The aqueous layer was further extracted with ethyl acetate(2×50 mL). The combined organics were dried (Na₂SO₄), filtered andconcentrated. The crude material was purified by column chromatography(silica gel, 90:9:1 ethyl acetate/methanol/concentrated ammoniumhydroxide) to affordN-(1-azabicyclo[2.2.2]oct-3-yl)-2-(4-nitrophenyl)benzoxazole-4-carboxamide(31 mg, 7%) as a yellow solid: ¹H NMR (500 MHz, CDCl₃) δ 9.35 (d, J=7.0Hz, 1H), 8.47-8.40 (m, 4H), 8.24 (dd, J=7.5, 1.0 Hz, 1H), 7.79 (dd,J=8.0, 0.5 Hz, 1H), 7.57 (t, J=8.0 Hz, 1H), 4.34-4.30 (m, 1H), 3.56-3.51(m, 1H), 3.12-2.86 (m, 4H), 2.85-2.77 (m, 1H), 2.19-2.14 (m, 1H),1.82-1.74 (m, 2H), 1.71-1.58 (m, 2H); MS (ESI+) m/z 393 (M+H); HPLC >99%(AUC), t_(R)=12.18 min.

Example 45 Preparation ofN-(1-Azabicyclo[2.2.2]oct-3-yl)-2-(4-aminophenyl)benzoxazole-4-carboxamide

To a solution ofN-(1-azabicyclo[2.2.2]oct-3-yl)-2-(4-nitrophenyl)benzoxazole-4-carboxamide(24 mg 0.06 mmol) in ethanol was added tin(II) chloride (116 mg, 0.61mmol). The reaction mixture was then heated to reflux for 4 h. Thereaction was cooled down to room temperature, then concentrated. Theresidue was dissolved in ethyl acetate (10 mL). The resulting solutionwas washed with 1 N NaOH (12 mL), water and brine, dried (Na₂SO₄),filtered and concentrated. The crude material was purified by columnchromatography (silica gel, 90:9:1 ethyl acetate/methanol/concentratedammonium hydroxide) to affordN-(1-azabicyclo[2.2.2]oct-3-yl)-2-(4-aminophenyl)benzoxazole-4-carboxamide(7 mg, 2%) as a yellow solid: ¹H NMR (500 MHz, CDCl₃) δ 9.68 (d, J=6.5Hz, 1H), 8.13 (d, J=8.0 Hz, 1H), 8.02 (d, J=8.5 Hz, 2H), 7.65 (d, J=8.0Hz, 1H), 7.39 (t, J=8.0 Hz, 1H), 6.79 (d, J=8.5 Hz, 2H), 4.40-4.36 (m,1H), 4.19-4.16 (m, 3H), 3.20-2.90 (m, 5H), 2.30-0.80 (m, 5H); MS (ESI+)m/z 363 (M+H); HPLC 96.0% (AUC), t_(R)=12.35 min.

Example 46 Preparation ofN-(1-Azabicyclo[2.2.2]oct-3-yl)-2-(4-acetylaminophenyl)benzoxazole-4-carboxamide

Step A: To a solution ofN-(1-azabicyclo[2.2.2]oct-3-yl)-2-(4-aminophenyl)benzoxazole-4-carboxamide(22 mg, 0.06 mmol) in dichloromethane was added acetic anhydride (10 μL,0.12 mmol), pyridine (15 μL, 0.18 mmol) and DMAP (1.5 mg, 0.01 mmol).The reaction mixture was stirred at room temperature for 3 h. Aceticanhydride (2 equiv) and pyridine (3 equiv) were re-filled and thereaction was stirred at room temperature for an additional 1.5 h. Themixture was diluted with ethyl acetate (20 mL), and then washed with asaturated solution of sodium bicarbonate. The aqueous layer was furtherextracted with ethyl acetate (2×50 mL). The combined organics were dried(Na₂SO₄), filtered and concentrated. The crude material was purified bycolumn chromatography (silica gel, 90:9:1 ethylacetate/methanol/concentrated ammonium hydroxide) and thenrecrystallized from acetonitrile to affordN-(1-azabicyclo[2.2.2]oct-3-yl)-2-(4-acetylaminophenyl)benzoxazole-4-carboxamide(11 mg, 44%) as a white solid: ¹H NMR (500 MHz, CDCl₃) δ 9.59-9.58 (m,1H), 8.17-8.16 (m, 3H), 7.77-7.69 (m, 4H), 7.46-7.43 (m, 1H), 7.39 (t,J=8.0 Hz, 1H), 4.40-4.33 (m, 1H), 2.26 (s, 3H), 3.58-3.53 (m, 1H),3.19-2.88 (m, 3H), 2.13-1.70 (m, 6H); MS (ESI+) m/z 405 (M+H); HPLC97.3% (AUC), t_(R)=13.85 min.

Example 47 Preparation ofN-(1-Azabicyclo[2.2.2]oct-3-yl)-2-(4-dimethylaminophenyl)benzoxazole-4-carboxamide

Step A: To a suspension of 2-amino-3-hydroxybenzoic acid hydrobromide(152 mg, 0.65 mmol) in dichloromethane (15 mL) was added pyridine (0.42ml, 5.2 mmol) followed by 4-dimethylaminobenzoyl chloride (358 mg, 1.95mmol). The resulting reaction mixture was stirred at room temperaturefor 15 min and DMAP (40 mg, 0.33 mmol) was added, then the reactionmixture was stirred at room temperature overnight. The reaction wasquenched with aqueous 1 N HCl (30 mL) until the solution reached pH 1.The solution was stirred for 30 min. The aqueous layer was extractedwith ethyl acetate. The organic layers were washed with brine, driedover Na₂SO₄, filtered and concentrated. The amide product was dissolvedin toluene (10 mL) and the solution was treated with p-toluenesulfonicacid monohydrate (200 mg, 1.05 mmol). The reaction mixture was thenheated to reflux overnight. The reaction was cooled down to roomtemperature, poured into water and extracted with ethyl acetate. Theorganic layer was separated then washed with water, brine, dried overNa₂SO₄, filtered and concentrated to a pale yellow solid. The crudeproduct was purified by column chromatography (silica gel, 9:1 to 2:1ethyl acetate/methanol) to afford the desired product (94 mg, 48%): MS(ESI+) m/z 283 (M+H).

Step B: A mixture of 2-(4-dimethylaminophenyl)benzoxazole-4-carboxylicacid from Step A (47 mg, 0.12 mmol), (±)-3-aminoquinuclidinedihydrochloride (40 mg, 0.20 mmol),1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (45 mg, 0.23mmol) and 1-hydroxybenzotriazole (63 mg, 0.47 mmol) in DMF (5 mL) wasstirred for 10 min at room temperature, then DIPEA (0.14 mL, 0.83 mmol)was added. The resulting reaction mixture was stirred at roomtemperature overnight. The mixture was diluted with ethyl acetate (20mL), and then washed with a saturated solution of sodium bicarbonate.The aqueous layer was further extracted with ethyl acetate (2×50 mL).The combined organics were dried (Na₂SO₄), filtered and concentrated.The crude material was purified by column chromatography (silica gel,90:9:1 ethyl acetate/methanol/concentrated ammonium hydroxide) andrecrystallized from acetonitrile and ethyl acetate to affordN-(1-azabicyclo[2.2.2]oct-3-yl)-2-(4-dimethylaminophenyl)benzoxazole-4-carboxamide(40 mg, 60%) as an off-white solid: ¹H NMR (500 MHz, CDCl₃) δ 9.74 (d,J=6.5 Hz, 1H), 8.13-8.04 (m, 3H), 7.63 (d, J=8.0 Hz, 1H), 7.36 (t, J=8.0Hz, 1H), 6.79 (d, J=9.0 Hz, 2H), 4.35-4.27 (m, 1H), 3.51 (t, J=12.0 Hz,1H), 3.11 (s, 6H), 2.96-2.82 (m, 3H), 2.22-2.11 (m, 2H), 1.80-1.50 (m,5H); MS (ESI+) m/z 391 (M+H); HPLC >99% (AUC), t_(R)=14.65 min.

Example 48 Preparation ofN-(9-Methyl-9-azabicyclo[3.3.1]non-3-yl)-2-(4-dimethylaminophenyl)benzoxazole-4-carboxamide

A mixture of 2-(4-dimethylaminophenyl)benzoxazole-4-carboxylic acid (78mg, 0.32 mmol), 3-amino-9-methyl-9-azabicyclo[3.3.1]nonanedihydrochloride (86 mg, 0.38 mmol),1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (86 mg, 0.45mmol) and 1-hydroxybenzotriazole (122 mg, 0.90 mmol) in DMF (5 mL) wasstirred for 10 min at room temperature, then DIPEA (0.26 mL, 1.6 mmol)was added. The resulting reaction mixture was stirred at roomtemperature overnight. The mixture was diluted with ethyl acetate (20mL), and then washed with a saturated solution of sodium bicarbonate.The aqueous layer was further extracted with ethyl acetate (2×50 mL).The combined organics were dried (Na₂SO₄), filtered and concentrated.The crude material was purified by column chromatography (silica gel,90:9:1 ethyl acetate/methanol/concentrated ammonium hydroxide) andrecrystallized from acetonitrile to affordN-(9-methyl-9-azabicyclo[3.3.1]non-3-yl)-2-(4-dimethylaminophenyl)benzoxazole-4-carboxamide(51 mg, 41%) as a yellow solid: ¹H NMR (500 MHz, CDCl₃) δ 9.21 (d, J=7.0Hz, 1H), 8.15-8.09 (m, 3H), 7.61 (d, J=8.0 Hz, 1H), 7.35 (t, J=8.0 Hz,1H), 6.80 (d, J=9.0 Hz, 2H), 4.61-4.54 (m, 1H), 3.10-3.15 (m, 8H),2.68-2.62 (m, 2H), 2.55 (s, 3H), 2.05-1.96 (m, 2H), 1.59-1.49 (m, 4H),1.22-1.19 (m, 1H); MS (ESI+) m/z 419 (M+H); HPLC 93.1% (AUC),t_(R)=16.55 mm.

Example 49 Preparation ofN-(9-Methyl-9-azabicyclo[3.3.1]non-3-yl)-2-(2-dimethylaminophenyl)benzoxazole-4-carboxamide

Step A: To an ice-cooled solution of 2-dimethylaminobenzoic acid (354mg, 2.14 mmol) in dichloromethane (15 mL) was added oxalyl chloride(0.18 mL, 2.14 mmol) dropwise, then the reaction mixture was stirred atroom temperature for 1 h. 2-Amino-3-hydroxybenzoic acid hydrobromide(0.50 g, 2.14 mmol) was added into the reaction mixture followed bytriethylamine (1.2 mL, 8.6 mmol). The resulting reaction mixture wasstirred at room temperature for 12 h, then diluted with dichloromethane,washed with brine, dried (Na₂SO₄), filtered and concentrated. The crudeproduct was dissolved in toluene (15 mL) and the solution was treatedwith p-toluenesulfonic acid monohydrate (610 mg, 3.21 mmol). Thereaction mixture was then heated to reflux overnight. The reaction wascooled down to room temperature, poured into water and extracted withethyl acetate. The organic layer was separated then washed with water,brine, dried over Na₂SO₄, filtered and concentrated. The crude productwas purified by column chromatography (silica gel, 9:1 to 3:1 ethylacetate/methanol) to afford the desired product (0.64 g, quantitative)as a yellow solid: ¹H NMR (500 MHz, DMSO-d₆) δ 7.92-7.78 (m, 3H),7.52-7.48 (m, 1H), 7.43 (t, J=7.5 Hz, 1H), 7.16-7.08 (m, 1H), 7.05-6.96(m, 1H), 2.82 (s, 1H), 2.70 (s, 6H); MS (ESI+) m/z 283 (M+H).

Step B: A mixture of benzoxazole carboxylic acid from Step A (100 mg,0.35 mmol), 3-amino-9-methyl-9-azabicyclo[3.3.1]nonane dihydrochloride(80 mg, 0.35 mmol), 1-ethyl-3-(3-dimethylaminopropyl)carbodiimidehydrochloride (134 mg, 0.70 mmol) and 1-hydroxybenzotriazole (95 mg,0.70 mmol) in DMF (1 mL) was stirred for 5 min at room temperature, thentriethylamine (0.19 mL, 1.4 mmol) was added. The resulting reactionmixture was stirred at room temperature for 12 h. The mixture wasdiluted with dichloromethane (20 mL), then washed with a saturatedsolution of sodium bicarbonate (10 mL). The aqueous layer was furtherextracted with dichloromethane (3×15 mL). The combined organics weredried (Na₂SO₄), filtered and concentrated. The crude material waspurified by column chromatography (silica gel, 89:10:1dichloromethane/methanol/concentrated ammonium hydroxide) followed byrecrystallization from ethyl acetate to affordN-(9-methyl-9-azabicyclo[3.3.1]non-3-yl)-2-(2-dimethylaminophenyl)benzoxazole-4-carboxamide(50 mg, 34%) as a yellow solid: ¹H NMR (500 MHz, CDCl₃) δ 9.13 (d, J=7.5Hz, 1H), 8.20 (dd, J=8.0, 1.0 Hz, 1H), 8.05 (dd, J=7.5, 1.5 Hz, 1H),7.69 (dd, J=8.0, 1.0 Hz, 1H), 7.50-7.42 (m, 2H), 7.14 (d, J=7.5 Hz, 1H),7.05 (t, J=8.0 Hz, 1H), 4.64-4.55 (m, 1H), 3.12 (d, J=10.5 Hz, 2H), 2.88(s, 6H), 2.65-2.58 (m, 2H), 2.53 (s, 3H), 2.12-1.95 (m, 3H), 1.60-1.52(m, 1H), 1.44 (t, J=10.5 Hz, 2H), 1.09 (d, J=12.5 Hz, 2H); MS (ESI+) m/z419 (M+H); HPLC >99% (AUC), t_(R)=13.95 min.

Example 50 Preparation of(S)-N-(1-Azabicyclo[2.2.2]oct-3-yl)-2-(2-dimethylaminophenyl)benzoxazole-4-carboxamide

A mixture of 2-(2-(dimethylamino)phenyl)benzo[d]oxazole-4-carboxylicacid (100 mg, 0.35 mmol), (S)-(−)-3-aminoquinuclidine dihydrochloride(70 mg, 0.35 mmol), 1-ethyl-3-(3-dimethylaminopropyl)carbodiimidehydrochloride (134 mg, 0.70 mmol) and 1-hydroxybenzotriazole (95 mg,0.70 mmol) in DMF (1 mL) was stirred for 5 min at room temperature, thentriethylamine (0.19 mL, 1.4 mmol) was added. The resulting reactionmixture was stirred at room temperature for 12 h. The mixture wasdiluted with dichloromethane (20 mL), then washed with a saturatedsolution of sodium bicarbonate (10 mL). The aqueous layer was furtherextracted with dichloromethane (3×15 mL). The combined organics weredried (Na₂SO₄), filtered and concentrated. The crude material waspurified by column chromatography (silica gel, 89:10:1dichloromethane/methanol/concentrated ammonium hydroxide) to afford(S)-N-(1-azabicyclo[2.2.2]oct-3-yl)-2-(2-dimethylaminophenyl)benzoxazole-4-carboxamide(46 mg, 34%) as a yellow solid: ¹H NMR (500 MHz, CDCl₃) δ 9.60 (d, J=7.0Hz, 1H), 8.19 (dd, J=7.5, 1.0 Hz, 1H), 7.99 (dd, J=8.0, 2.0 Hz, 1H),7.71 (dd, J=8.0, 1.0 Hz, 1H), 7.49-7.42 (m, 2H), 7.13 (d, J=8.5 Hz, 1H),7.03 (t, J=8.5 Hz, 1H), 4.28-4.26 (m, 1H), 3.49 (ddd, J=11.5, 9.5, 2.0Hz, 1H), 3.10-2.85 (m, 4H), 2.85 (s, 6H), 2.77 (dd, J=14.0, 4.5 Hz, 1H),2.15-2.11 (m, 1H), 2.04-1.98 (m, 1H), 1.78-1.70 (m, 2H), 1.60-1.51 (m,1H); MS (ESI+) m/z 391 (M+H); HPLC >99% (AUC), t_(R)=12.81 min.

Example 51 Preparation ofN-(9-Methyl-9-azabicyclo[3.3.1]non-3-yl)-6-chloro-2-(2-dimethylaminophenyl)benzoxazole-4-carboxamide

Step A: To an ice-cooled solution of 2-dimethylaminobenzoic acid (439mg, 2.66 mmol) in dichloromethane (15 mL) was added oxalyl chloride(0.23 mL, 2.66 mmol) dropwise, then the reaction mixture was stirred atroom temperature for 1 h. 2-Amino-5-chloro-3-hydroxybenzoic acid (0.50g, 2.66 mmol) was added into the reaction mixture followed bytriethylamine (1.1 mL, 8.0 mmol). The resulting reaction mixture wasstirred at room temperature for 12 h, then diluted with dichloromethane,washed with brine, dried (Na₂SO₄), filtered and concentrated. The crudeproduct was dissolved in toluene (18 mL) and the solution was treatedwith p-toluenesulfonic acid monohydrate (506 mg, 2.66 mmol). Thereaction mixture was then heated to reflux overnight. The reaction wascooled down to room temperature, poured into water and extracted withethyl acetate. The organic layer was separated then washed with water,brine, dried over Na₂SO₄, filtered and concentrated. The crude productwas purified by column chromatography (silica gel, 9:1 to 3:1 ethylacetate/methanol) to afford the desired product (0.57 g, 68%) as a brownsolid: ¹H NMR (500 MHz, DMSO-d₆) δ 7.92 (d, J=7.5 Hz, 1H), 7.81 (d,J=7.5 Hz, 1H), 7.67-7.57 (m, 2H), 7.35-7.28 (m, 1H), 6.99 (t, J=7.5 Hz,1H), 2.77 (s, 1H), 2.69 (s, 6H); MS (ESI+) m/z 317 (M+H).

Step B: A mixture of benzoxazole carboxylic acid from Step A (100 mg,0.32 mmol), 3-amino-9-methyl-9-azabicyclo[3.3.1]nonane dihydrochloride(73 mg, 0.32 mmol), 1-ethyl-3-(3-dimethylaminopropyl)carbodiimidehydrochloride (123 mg, 0.64 mmol) and 1-hydroxybenzotriazole (86 mg,0.64 mmol) in DMF (1.5 mL) was stirred for 5 min at room temperature,then triethylamine (0.17 mL, 1.3 mmol) was added. The resulting reactionmixture was stirred at room temperature for 12 h. The mixture wasdiluted with dichloromethane (20 mL), then washed with a saturatedsolution of sodium bicarbonate (10 mL). The aqueous layer was furtherextracted with dichloromethane (3×15 mL). The combined organics weredried (Na₂SO₄), filtered and concentrated. The crude material waspurified by column chromatography (silica gel, 89:10:1dichloromethane/methanol/concentrated ammonium hydroxide) to affordN-(9-methyl-9-azabicyclo[3.3.1]non-3-yl)-6-chloro-2-(2-dimethylaminophenyl)benzoxazole-4-carboxamide(33 mg, 23%) as a yellow solid: ¹H NMR (500 MHz, CDCl₃) δ 9.01 (d, J=7.5Hz, 1H), 8.18 (d, J=2.0 Hz, 1H), 8.03 (dd, J=8.0, 2.0 Hz, 1H), 7.68 (d,J=1.5 Hz, 1H), 7.50-7.46 (m, 1H), 7.14 (d, J=8.0 Hz, 1H), 7.05 (t, J=8.0Hz, 1H), 4.63-4.53 (m, 1H), 3.12 (d, J=11.0 Hz, 2H), 2.88 (s, 6H),2.65-2.57 (m, 2H), 2.52 (s, 3H), 2.08-1.95 (m, 3H), 1.60-1.54 (m, 1H),1.42 (td, J=13.5, 3.0 Hz, 2H), 1.07 (d, J=12.5 Hz, 2H); MS (ESI+) m/z453 (M+H); HPLC >99% (AUC), t_(R)=13.42 min.

Example 52 Preparation of(S)-N-(1-Azabicyclo[2.2.2]oct-3-yl)-6-chloro-2-(2-dimethylaminophenyl)benzoxazole-4-carboxamide

A mixture of 2-(2-(dimethylamino)phenyl)benzo[d]oxazole-4-carboxylicacid (100 mg, 0.32 mmol), (S)-(−)-3-aminoquinuclidine dihydrochloride(64 mg, 0.32 mmol), 1-ethyl-3-(3-dimethylaminopropyl)carbodiimidehydrochloride (123 mg, 0.64 mmol) and 1-hydroxybenzotriazole (86 mg,0.64 mmol) in DMF (1.5 mL) was stirred for 5 min at room temperature,then triethylamine (0.17 mL, 1.28 mmol) was added. The resultingreaction mixture was stirred at room temperature for 12 h. The mixturewas diluted with dichloromethane (20 mL), then washed with a saturatedsolution of sodium bicarbonate (10 mL). The aqueous layer was furtherextracted with dichloromethane (3×15 mL). The combined organics weredried (Na₂SO₄), filtered and concentrated. The crude material waspurified by column chromatography (silica gel, 89:10:1dichloromethane/methanol/concentrated ammonium hydroxide) to afford the(S)-N-(1-azabicyclo[2.2.2]oct-3-yl)-6-chloro-2-(2-dimethylaminophenyl)benzoxazole-4-carboxamide(43 mg, 32%) as a yellow solid: ¹H NMR (500 MHz, CDCl₃) δ 9.47 (d, J=7.5Hz, 1H), 8.17 (d, J=2.0 Hz, 1H), 7.97 (dd, J=8.0, 1.5 Hz, 1H), 7.71 (d,J=2.0 Hz, 1H), 7.50-7.45 (m, 1H), 7.13 (d, J=8.5 Hz, 1H), 7.02 (t, J=8.0Hz, 1H), 4.28-4.25 (m, 1H), 3.49 (ddd, J=11.5, 9.5, 2.0 Hz, 1H),3.08-2.84 (m, 4H), 2.84 (s, 6H), 2.76 (dd, J=14.0, 4.5 Hz, 1H),2.13-2.10 (m, 1H), 1.99-1.94 (m, 1H), 1.76-1.68 (m, 2H), 1.58-1.52 (m,1H); MS (ESI+) m/z 425 (M+H); HPLC >99% (AUC), t_(R)=13.47 min.

Example 53 Preparation ofN-(1-Azabicyclo[2.2.2]oct-3-yl)-2-(4-cyanophenyl)benzoxazole-4-carboxamide

Step A: To a suspension of 2-amino-3-hydroxybenzoic acid (200 mg, 0.85mmol) in dichloromethane (30 mL) was added pyridine (0.55 mL, 6.84 mmol)followed by 4-cyanobenzoyl chloride (566 mg, 3.42 mmol) at roomtemperature. The resulting reaction mixture was stirred at roomtemperature for 15 min then DMAP (11 mg, 0.09 mmol) was added and thereaction mixture was stirred at room temperature overnight. The reactionwas quenched with aqueous 1 N HCl (30 mL) until the solution reachedpH 1. The solution was stirred for 30 min. The aqueous layer wasextracted with ethyl acetate. The organic layers were washed with brine,dried over Na₂SO₄, filtered and concentrated to give an orange solid.The product was dissolved in toluene (15 mL) and the solution treatedwith p-toluenesulfonic acid monohydrate (331 mg, 1.74 mmol). Thereaction mixture was then heated to reflux overnight. The reaction wascooled down to room temperature, poured into water and extracted withethyl acetate. The organic layer was separated then washed with water,brine, dried over Na₂SO₄, filtered and concentrated to an orange solid.The crude product was purified by column chromatography (silica gel, 9:1to 2:1 ethyl acetate/methanol) to afford the desired product (577 mg,quantitative) as a pale orange solid: MS (ESI+) m/z 265 (M+H).

Step B: A mixture of 2-(4-cyanophenyl)benzoxazole-4-carboxylic acid fromStep A (289 mg, 1.09 mmol), 3-aminoquinuclidine dihydrochloride (261 mg,1.31 mmol), 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride(418 mg, 2.19 mmol) and 1-hydroxybenzotriazole (296 mg, 2.19 mmol) inDMF (15 mL) was stirred for 10 min at room temperature, then DIPEA (0.90mL, 5.47 mmol) was added. The resulting reaction mixture was stirred atroom temperature overnight. The mixture was diluted with ethyl acetateand then washed with a saturated solution of sodium bicarbonate. Theaqueous layer was further extracted with ethyl acetate. The combinedorganics were dried (Na₂SO₄), filtered and concentrated. The crudematerial was purified by column chromatography (silica gel, 90:9:1 ethylacetate/methanol/concentrated ammonium hydroxide) to affordN-(1-azabicyclo[2.2.2]oct-3-yl)-2-(4-cyanophenyl)benzoxazole-4-carboxamide(7 mg, 2%) as a white solid: ¹H NMR (500 MHz, CDCl₃) δ 9.35 (d, J=7.5Hz, 1H), 8.35 (d, J=8.5 Hz, 2H), 8.25 (d, J=7.5, Hz, 1H), 7.88 (d,J=8.5, Hz, 2H), 7.77 (d, J=7.5 Hz, 1H), 7.56 (t, J=8.0 Hz, 1H),4.36-4.26 (m, 1H), 3.58-3.47 (m, 1H), 3.12-3.00 (m, 2H), 2.97-2.89 (m,2H), 2.86-2.79 (m, 1H), 2.30-2.00 (m, 2H), 1.82-1.75 (m, 3H); MS (ESI+)m/z 373 (M+H); HPLC 94.3% (AUC), t_(R)=12.18 min.

Example 54 Preparation ofN-(1-Azabicyclo[2.2.2]oct-3-yl)-2-(4-iodophenyl)benzoxazole-4-carboxamide

Step A: To a solution of methyl 3-hydroxyanthranilate (550 mg, 3.29mmol) in methylene chloride (20 mL) was added 4-iodobenzoyl chloride(2.63 g, 9.87 mmol) followed by pyridine (1.06 mL, 13.2 mmol) and DMAP(40 mg, 0.33 mmol) at room temperature. The resulting mixture wasstirred under nitrogen at room temperature overnight and then thereaction mixture was quenched with a saturated solution of sodiumbicarbonate (100 mL) with stirring at room temperature for 30 min. Theorganic layer was separated and the aqueous layer was extracted withmethylene chloride. The combined organic layers were washed with brine,dried over sodium sulfate, filtered and concentrated in vacuo. Theresidue was dissolved in toluene (20 mL) and the solution was treatedwith p-toluenesulfonic acid monohydrate (600 mg, 3.16 mmol). Thereaction mixture was then heated at reflux under nitrogen overnight. Thereaction mixture was cooled to room temperature, diluted with ethylacetate, washed with a saturated solution of sodium bicarbonate andbrine, dried over sodium sulfate, filtered and concentrated. The crudematerial was purified by column chromatography (silica gel, 4:1hexanes/ethyl acetate) to afford the methyl ester (274 mg, 23%) as anoff-white solid: ¹H NMR (300 MHz, CDCl₃) δ 8.10 (dt, J=8.5, 2.0 Hz, 2H),8.07 (dd, J=8.0, 1.0 Hz, 1H), 7.92 (dt, J=8.5, 2.0 Hz, 2H), 7.81 (dd,J=8.0, 1.0 Hz, 1H), 7.47 (t, J=8.0 Hz, 1H), 4.09 (s, 3H); MS (ESI+) m/z380 (M+H).

Step B: To a solution of the methyl ester from Step A (0.4 g, 1.05 mmol)in THF (5 mL) was added 1 N NaOH (3 mL, 3 mmol), and then the reactionmixture was stirred at room temperature for 12 h. The reaction mixturewas acidified with 1 N HCl (pH=1), then extracted with methylenechloride. The combined organic layers were dried (Na₂SO₄), filtered andconcentrated to provide the carboxylic acid (0.4 g, quantitative) as anoff-white solid: ¹H NMR (500 MHz, CDCl₃) δ 11.00 (br s, 1H), 8.18 (dd,J=8.0, 1.0 Hz, 1H), 8.01 (dt, J=8.5, 2.0 Hz, 2H), 7.96 (dt, J=8.5, 2.0Hz, 2H), 7.84 (dd, J=8.0, 1.0 Hz, 1H), 7.55 (t, J=8.0 Hz, 1H); MS (ESI+)m/z 366 (M+H).

Step C: A mixture of the carboxylic acid from Step B (190 mg, 0.52mmol), (±)-3-aminoquinuclidine dihydrochloride (124 mg, 0.624 mmol),1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (199 mg,1.04 mmol) and 1-hydroxybenzotriazole (140 mg, 1.04 mmol) in DMF (10 mL)was stirred under nitrogen at room temperature for 10 min, and thentriethylamine (0.29 mL, 2.08 mmol) was added. The resulting reactionmixture was stirred at room temperature overnight, and then was quenchedwith a saturated solution of sodium bicarbonate, extracted withmethylene chloride. The combined organic layers were dried (Na₂SO₄),filtered and concentrated. The crude material was purified by columnchromatography (silica gel, 90:10:1 ethyl acetate/methanol/concentratedammonium hydroxide) to affordN-(1-azabicyclo[2.2.2]oct-3-yl)-2-(4-iodophenyl)benzoxazole-4-carboxamide(150 mg, 61%) as a white solid: ¹H NMR (500 MHz, CDCl₃) δ 9.47 (d, J=7.0Hz, 1H), 8.20 (dd, J=8.0, 1.0 Hz, 1H), 7.94 (s, 4H), 7.72 (dd, J=8.0,1.0 Hz, 1H), 7.49 (t, J=8.0 Hz, 1H), 4.36-4.29 (m, 1H), 3.53 (ddd,J=14.0, 9.5, 2.0 Hz, 1H), 3.12-2.82 (m, 5H), 2.18-2.02 (m, 2H),1.80-1.65 (m, 3H); MS (ESI+) m/z 474 (M+H); HPLC >99% (AUC), t_(R)=13.35min.

Example 55 Preparation ofN-(1-Azabicyclo[2.2.2]oct-3-yl)-2-(4-trimethylsilylethynylphenyl)benzoxazole-4-carboxamide

To a solution ofN-(1-azabicyclo[2.2.2]oct-3-yl)-2-(4-iodophenyl)benzoxazole-4-carboxamide(50 mg, 0.11 mmol) in DMF (1 mL) and triethylamine (1 mL),(trimethylsilyl)acetylene (0.045 mL, 0.33 mmol) was added at roomtemperature followed by copper(I) iodide (4.2 mg, 0.022 mmol) andbis(triphenylphosphine)dichloropalladium(II) (7.7 mg, 0.011 mmol). Theresulting mixture was stirred under nitrogen at room temperature for 1h, and then was quenched with water, extracted with methylene chloride.The combined organic layers were washed with water and brine, dried(Na₂SO₄), filtered and concentrated. The crude material was purified bycolumn chromatography (silica gel, 90:10:1 ethylacetate/methanol/concentrated ammonium hydroxide) to affordN-(1-azabicyclo[2.2.2]oct-3-yl)-2-(4-trimethylsilylethynylphenyl)benzoxazole-4-carboxamide(44 mg, 94%) as a light yellow solid: ¹H NMR (500 MHz, CDCl₃) δ 9.51 (d,J=7.0 Hz, 1H), 8.20 (dd, J=8.0, 1.0 Hz, 1H), 8.17 (d, J=8.0 Hz, 2H),7.72 (dd, J=8.0, 1.0 Hz, 1H), 7.64 (d, J=8.0 Hz, 2H), 7.49 (t, J=8.0 Hz,1H), 4.32-4.29 (m, 1H), 3.52 (ddd, J=14.0, 9.5, 2.0 Hz, 1H), 3.12-2.76(m, 5H), 2.18-2.02 (m, 2H), 1.80-1.62 (m, 3H), 0.29 (s, 9H); MS (ESI+)m/z 444 (M+H); HPLC >99% (AUC), t_(R)=14.91 min.

Example 56 Preparation ofN-(1-Azabicyclo[2.2.2]oct-3-yl)-2-(4-propyn-1-ylphenyl)benzoxazole-4-carboxamide

Zinc chloride (1.0 M in ether, 0.33 mL, 0.33 mmol) was added dropwise toa solution of 1-propynylmagnesium bromide in THF (0.5 M in THF, 0.66 mL,0.33 mmol) at room temperature and the mixture was stirred undernitrogen for 10 min.N-(1-Azabicyclo[2.2.2]oct-3-yl)-2-(4-iodophenyl)benzoxazole-4-carboxamide(50 mg, 0.11 mmol) in DMF (2 mL) was added followed bybis(triphenylphosphine)dichloropalladium(II) (7.7 mg, 0.011 mmol). Theresulting mixture was stirred under nitrogen at room temperature for 2h, and then was quenched with saturated ammonium chloride, extractedwith methylene chloride. The combined organic layers were washed withwater and brine, dried (Na₂SO₄), filtered and concentrated. The crudematerial was purified by column chromatography (silica gel, 90:10:1ethyl acetate/methanol/concentrated ammonium hydroxide) to affordN-(1-azabicyclo[2.2.2]oct-3-yl)-2-(4-propyn-1-ylphenyl)benzoxazole-4-carboxamide(36 mg, 88%) as a light yellow solid: ¹H NMR (300 MHz, CDCl₃) δ 9.56 (d,J=7.0 Hz, 1H), 8.23 (dd, J=8.0, 1.0 Hz, 1H), 8.17 (d, J=8.4 Hz, 2H),7.73 (dd, J=8.0, 1.0 Hz, 1H), 7.58 (d, J=8.4 Hz, 2H), 7.49 (t, J=8.0 Hz,1H), 4.35-4.29 (m, 1H), 3.54 (ddd, J=14.0, 9.5, 2.0 Hz, 1H), 3.16-2.82(m, 5H), 2.20-2.03 (m, 2H), 2.14 (s, 3H), 1.80-1.60 (m, 3H); MS (ESI+)m/z 386 (M+H); HPLC >99% (AUC), t_(R)=13.24 min.

Example 57 Preparation ofN-(1-Azabicyclo[2.2.2]oct-3-yl)-2-(4-ethynylphenyl)benzoxazole-4-carboxamide

A mixture ofN-(1-azabicyclo[2.2.2]oct-3-yl)-2-(4-trimethylsilylethynylphenyl)benzoxazole-4-carboxamide(20 mg, 0.045 mmol), potassium carbonate (20 mg, 0.14 mmol) and methanol(1 mL) was stirred at room temperature for 2 h, and then was dilutedwith ethyl acetate, washed with water and brine, dried (Na₂SO₄),filtered and concentrated. The crude material was purified by columnchromatography (silica gel, 90:10:1 ethyl acetate/methanol/concentratedammonium hydroxide) to affordN-(1-azabicyclo[2.2.2]oct-3-yl)-2-(4-ethynylphenyl)benzoxazole-4-carboxamide(14 mg, 84%) as a white solid: ¹H NMR (500 MHz, CDCl₃) δ 9.49 (d, J=7.0Hz, 1H), 8.22-8.18 (m, 3H), 7.73 (dd, J=8.0, 1.0 Hz, 1H), 7.68 (d, J=8.5Hz, 2H), 7.48 (t, J=8.0 Hz, 1H), 4.35-4.31 (m, 1H), 3.53 (ddd, J=14.0,9.5, 2.0 Hz, 1H), 3.30 (s, 1H), 3.15-2.82 (m, 5H), 2.20-2.03 (m, 2H),1.80-1.62 (m, 3H); MS (ESI+) m/z 372 (M+H); HPLC >99% (AUC), t_(R)=12.77min.

Example 58 Preparation ofN-(1-Azabicyclo[2.2.2]oct-3-yl)-2-biphenyl-4-ylbenzoxazole-4-carboxamide

To a mixture ofN-(1-azabicyclo[2.2.2]oct-3-yl)-2-(4-iodophenyl)benzoxazole-4-carboxamide(30 mg, 0.063 mmol), phenylboronic acid (12 mg, 0.098 mmol), 2 M Na₂CO₃(2 mL) and toluene (2 mL) was deoxygenated with nitrogen for 10 min, andthen tetrakis(triphenylphosphine)palladium(0) (7.3 mg, 0.0063 mmol) wasadded. The resulting mixture was heated at 80° C. under nitrogenovernight, and then was cooled to room temperature, quenched withsaturated sodium bicarbonate, extracted with methylene chloride. Thecombined organic layers were washed with brine, dried (Na₂SO₄), filteredand concentrated. The crude material was purified by columnchromatography (silica gel, 90:10:1 ethyl acetate/methanol/concentratedammonium hydroxide) to affordN-(1-azabicyclo[2.2.2]oct-3-yl)-2-biphenyl-4-ylbenzoxazole-4-carboxamide(21 mg, 78%) as a light yellow solid: ¹H NMR (500 MHz, CDCl₃) δ 9.60 (d,J=7.0 Hz, 1H), 8.31 (d, J=8.0 Hz, 2H), 8.21 (d, J=7.5 Hz, 1H), 7.80 (d,J=8.0 Hz, 2H), 7.74 (d, J=7.5 Hz, 1H), 7.69-7.67 (m, 2H), 7.52-7.42 (m,4H), 4.36-4.30 (m, 1H), 3.53 (ddd, J=14.0, 9.5, 2.0 Hz, 1H), 3.17-2.84(m, 5H), 2.19-2.10 (m, 2H), 1.80-1.63 (m, 3H); MS (ESI+) m/z 424 (M+H);HPLC 96.3% (AUC), t_(R)=14.01 min.

Example 59 Preparation ofN-(1-Azabicyclo[2.2.2]oct-3-yl)-2-(4-phenoxyphenyl)benzoxazole-4-carboxamide

A mixture ofN-(1-azabicyclo[2.2.2]oct-3-yl)-2-(4-iodophenyl)benzoxazole-4-carboxamide(35 mg, 0.074 mmol), phenol (14 mg, 0.15 mmol), copper(I) bromide (2 mg,0.014 mmol), cesium carbonate (49 mg, 0.15 mmol) and pyridine (1 mL) washeated at 130° C. under nitrogen overnight, and then was cooled to roomtemperature, quenched with saturated sodium bicarbonate, extracted withmethylene chloride. The combined organic layers were washed with brine,dried (Na₂SO₄), filtered and concentrated. The crude material waspurified by semi-preparative HPLC to affordN-(1-azabicyclo[2.2.2]oct-3-yl)-2-(4-phenoxyphenyl)benzoxazole-4-carboxamide(16 mg, 50%) as a light yellow solid: ¹H NMR (500 MHz, CDCl₃) δ 9.66 (d,J=7.0 Hz, 1H), 8.20-8.17 (m, 3H), 7.70 (dd, J=8.0, 1.0 Hz, 1H),7.47-7.42 (m, 3H), 7.23 (t, J=8.0 Hz, 1H), 7.14-7.11 (m, 4H), 4.35-4.28(m, 1H), 3.52 (ddd, J=14.0, 9.5, 2.0 Hz, 1H), 3.09-2.81 (m, 5H),2.17-2.07 (m, 2H), 1.80-1.62 (m, 3H); MS (ESI+) m/z 440 (M+H); HPLC >99%(AUC), t_(R)=13.81 min.

Example 60 Preparation ofN-(1-Azabicyclo[2.2.2]oct-3-yl)-2-(4-phenylaminophenyl)benzoxazole-4-carboxamide

A mixture ofN-(1-azabicyclo[2.2.2]oct-3-yl)-2-(4-iodophenyl)benzoxazole-4-carboxamide(27 mg, 0.057 mmol), aniline (10.4 μL, 0.114 mmol), palladium acetate(1.3 mg, 0.0057 mmol), racemic BINAP (10.6 mg, 0.017 mmol) and toluene(2 mL) was stirred under nitrogen at room temperature for 30 min. Cesiumcarbonate (37 mg, 0.11 mmol) was added and the mixture was heated at110° C. under nitrogen for 5 h. The mixture was cooled to roomtemperature, quenched with saturated aqueous sodium bicarbonate,extracted with methylene chloride. The combined organic layers werewashed with brine, dried (Na₂SO₄), filtered and concentrated. The crudematerial was purified by semi-preparative HPLC to affordN-(1-azabicyclo[2.2.2]oct-3-yl)-2-(4-phenylaminophenyl)benzoxazole-4-carboxamide(21 mg, 84%) as a light yellow solid: ¹H NMR (500 MHz, CDCl₃) δ 9.66 (d,J=7.5 Hz, 1H), 8.15 (dd, J=8.0, 1.0 Hz, 1H), 8.09 (dd, J=7.5, 2.0 Hz,2H), 7.66 (dd, J=8.0, 1.0 Hz, 1H), 7.41-7.36 (m, 3H), 7.22 (d, J=7.5 Hz,2H), 7.12-7.10 (m, 3H), 6.15 (s, 1H), 4.32-4.28 (m, 1H), 3.52 (ddd,J=14.0, 9.5, 2.0 Hz, 1H), 3.10-2.81 (m, 5H), 2.17-2.06 (m, 2H),1.78-1.64 (m, 3H); MS (ESI+) m/z 439 (M+H); HPLC >99% (AUC), t_(R)=14.32min.

Example 61 Preparation ofN-(9-Methyl-9-azabicyclo[3.3.1]non-3-yl)-2-benzo[1,3]dioxol-5-ylbenzoxazole-4-carboxamide

Step A: To a suspension of 2-amino-3-hydroxybenzoic acid (152 mg, 0.65mmol) in dichloromethane (15 mL) was added pyridine (0.42 mL, 5.2 mmol)followed by piperonyloyl chloride (310 mg, 1.95 mmol). The resultingreaction mixture was stirred at room temperature for 15 min, then DMAP(16 mg, 0.13 mmol) was added and the reaction mixture was stirred atroom temperature overnight. The reaction was quenched with aqueous 1 NHCl (20 mL) until the solution reached pH 1. The solution was stirredfor 30 min. The aqueous layer was extracted with ethyl acetate. Theorganic layers were washed with brine and dried over Na₂SO₄, filteredand concentrated to a yellow solid. The product was directlyre-dissolved in toluene (10 mL) and the solution was treated withp-toluenesulfonic acid monohydrate (177 mg, 0.93 mmol). The reactionmixture was then heated to reflux overnight. The reaction was cooleddown to room temperature, poured into water and extracted with ethylacetate. The organic layer was separated then washed with water, brine,dried over Na₂SO₄, filtered and concentrated to a yellow solid. Thecrude product was purified by column chromatography (silica gel, 9:1 to2:1 ethyl acetate/methanol) to afford the desired product (82 mg, 46%)as a pale orange solid: ¹H NMR (500 MHz, CD₃OD) δ 7.90 (dd, J=7.5, 1.0Hz, 1H), 7.63-7.58 (m, 2H), 7.54 (d, J=1.5 Hz, 1H), 7.39 (t, J=8.0 Hz,1H), 6.72 (d, J=8.5 Hz, 1H), 5.97 (s, 2H); MS (ESI+) m/z 284 (M+H).

Step B: A mixture of 2-benzo[1,3]dioxol-5-ylbenzoxazole-4-carboxylicacid from Step A (82 mg, 0.29 mmol),3-amino-9-methyl-9-azabicyclo[3.3.1]nonane dihydrochloride (80 mg, 0.35mmol), 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (78mg, 0.58 mmol) and 1-hydroxybenzotriazole (111 mg, 0.82 mmol) in DMF (5mL) was stirred for 10 min at room temperature, then DIPEA (0.19 mL,1.45 mmol) was added. The resulting reaction mixture was stirred at roomtemperature overnight. The mixture was diluted with ethyl acetate (20mL), and then washed with a saturated solution of sodium bicarbonate.The aqueous layer was further extracted with ethyl acetate (2×50 mL).The combined organics were dried (Na₂SO₄), filtered and concentrated.The crude material was purified by column chromatography (silica gel,90:9:1 ethyl acetate/methanol/concentrated ammonium hydroxide) to affordN-(9-methyl-9-azabicyclo[3.3.1]non-3-yl)-2-benzo[1,3]dioxol-5-ylbenzoxazole-4-carboxamide(84 mg, 69%) as a white solid: ¹H NMR (500 MHz, CDCl₃) δ 9.01 (d, J=7.0Hz, 1H), 8.19 (dd, J=7.5, 1.0 Hz, 1H), 7.84 (dd, J=8.0, 1.5 Hz, 1H),7.67-7.64 (m, 2H), 7.42 (t, J=8.0 Hz, 1H), 6.99 (d, J=8.0 Hz, 1H), 6.12(s, 2H), 4.63-4.54 (m, 1H), 3.16-3.11 (m, 2H), 2.68-2.61 (m, 2H), 2.55(s, 3H), 2.19-2.00 (m, 3H), 1.61-1.48 (m, 4H), 1.21-1.18 (m, 1H); MS(ESI+) m/z 420 (M+H); HPLC 98.2% (AUC), t_(R)=13.15 min.

Example 62 Preparation of(S)-N-(1-Azabicyclo[2.2.2]oct-3-yl)-2-benzo[1,3]dioxol-5-yl-benzoxazole-4-carboxamide

A mixture of 2-benzo[1,3]dioxol-5-yl-benzoxazole-4-carboxylic acid (29mg, 0.10 mmol), (S)-3-aminoquinuclidine dihydrochloride (24 mg, 0.12mmol), 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (38mg, 0.20 mmol) and 1-hydroxybenzotriazole (27 mg, 0.20 mmol) in DMF (5mL) was stirred for 10 min at room temperature, then DIPEA (66 μL, 0.40mmol) was added. The resulting reaction mixture was stirred at roomtemperature overnight. The mixture was diluted with ethyl acetate (20mL), and then washed with a saturated solution of sodium bicarbonate.The aqueous layer was further extracted with ethyl acetate (2×50 mL).The combined organics were dried (Na₂SO₄), filtered and concentrated.The crude material was purified by column chromatography (silica gel,90:9:1 ethyl acetate/methanol/concentrated ammonium hydroxide) to afford(S)-N-(1-azabicyclo[2.2.2]oct-3-yl)-2-benzo[1,3]dioxol-5-yl-benzoxazole-4-carboxamide(17 mg, 42%) as a white solid: ¹H NMR (500 MHz, CDCl₃) δ 9.54 (d, J=7.0Hz, 1H), 8.17 (dd, J=7.5, 1.0 Hz, 1H), 7.82 (dd, J=8.0, 1.5 Hz, 1H),7.68 (dd, J=8.0, 1.0 Hz, 1H), 7.64 (d, J=1.5 Hz, 1H), 7.44 (t, J=8.0 Hz,1H), 6.98 (d, J=8.5 Hz, 1H), 6.11 (s, 2H), 4.33-4.29 (m, 1H), 3.56-3.48(m, 1H), 3.13-2.99 (m, 2H), 2.95-2.88 (m, 2H), 2.85-2.79 (m, 1H),2.18-2.13 (m, 1H), 1.80-1.59 (m, 4H); MS (ESI+) m/z 392 (M+H); HPLC97.4% (AUC), t_(R)=12.51 min.

Example 63 Preparation ofN-(1-Azabicyclo[2.2.2]oct-3-yl)-2-benzofuran-5-ylbenzoxazole-4-carboxamide

Step A: To a suspension of 3-hydroxyanthranilic acid (70 mg, 0.46 mmol)in methylene chloride (4 mL) was added 1-benzofuran-5-carbonyl chloride(250 mg, 1.38 mmol) followed by pyridine (0.15 mL, 1.83 mmol) and DMAP(6 mg, 0.049 mmol) at room temperature. The resulting mixture wasstirred under nitrogen at room temperature overnight and then thereaction mixture was quenched with 2 N HCl (40 mL), extracted withmethylene chloride. The combined organic layers were washed with brine,dried over sodium sulfate, filtered and concentrated in vacuo. Theresidue was dissolved in toluene (10 mL) and the resulting solution wastreated with p-toluenesulfonic acid monohydrate (87 mg, 0.46 mmol). Thereaction mixture was then heated at reflux under nitrogen overnight. Thereaction mixture was cooled to room temperature, diluted with ethylacetate, washed with water and brine, dried over sodium sulfate,filtered and concentrated. The crude material was purified by columnchromatography (silica gel, 9:1 to 3:1 ethyl acetate/methanol) to affordthe carboxylic acid (76 mg, 60%) as a white solid: ¹H NMR (300 MHz,CDCl₃) δ 11.50 (br s, 1H), 8.60 (d, J=1.2 Hz, 1H), 8.28 (dd, J=8.4, 1.5Hz, 1H), 8.16 (dd, J=7.8, 1.2 Hz, 1H), 7.84 (dd, J=8.4, 1.2 Hz, 1H),7.77 (d, J=2.4 Hz, 1H), 7.70 (d, J=7.8 Hz, 1H), 7.51 (t, J=8.4 Hz, 1H),6.94 (dd, J=2.4, 1.2 Hz, 1H); MS (ESI+) m/z 280 (M+H).

Step B: A mixture of the carboxylic acid from Step A (76 mg, 0.27 mmol),(±)-3-aminoquinuclidine dihydrochloride (65 mg, 0.33 mmol),1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (103 mg,0.54 mmol) and 1-hydroxybenzotriazole (73 mg, 0.54 mmol) in DMF (5 mL)was stirred under nitrogen at room temperature for 10 min, and thentriethylamine (0.15 mL, 1.08 mmol) was added. The resulting reactionmixture was stirred at room temperature for 15 h, and then was quenchedwith a saturated solution of sodium bicarbonate, extracted withmethylene chloride. The combined organic layers were dried (Na₂SO₄),filtered and concentrated. The crude material was purified by columnchromatography (silica gel, 90:10:1 ethyl acetate/methanol/concentratedammonium hydroxide) to affordN-(1-azabicyclo[2.2.2]oct-3-yl)-2-benzofuran-5-ylbenzoxazole-4-carboxamide(77 mg, 73%) as a white solid: ¹H NMR (300 MHz, CDCl₃) δ 9.62 (d, J=7.2Hz, 1H), 8.51 (d, J=1.5 Hz, 1H), 8.21 (dd, J=8.4, 1.5 Hz, 1H), 8.19 (dd,J=7.8, 1.2 Hz, 1H), 7.76 (d, J=2.4 Hz, 1H), 7.73 (dd, J=8.4, 1.2 Hz,1H), 7.68 (d, J=8.7 Hz, 1H), 7.46 (t, J=8.1 Hz, 1H), 6.93 (dd, J=2.4,1.2 Hz, 1H), 4.38-4.32 (m, 1H), 3.55 (ddd, J=14.1, 9.3, 2.1 Hz, 1H),3.21-2.86 (m, 5H), 2.25-2.09 (m, 2H), 1.83-1.67 (m, 3H); MS (ESI+) m/z388 (M+H); HPLC >99% (AUC), t_(R)=12.89 min.

Example 64 Preparation ofN-(1-Azabicyclo[2.2.2]oct-3-yl)-2-(2,3-dihydrobenzofuran-5-yl)benzoxazole-4-carboxamide

A mixture ofN-(1-azabicyclo[2.2.2]oct-3-yl)-2-benzofuran-5-ylbenzoxazole-4-carboxamide(30 mg, 0.077 mmol), 10% palladium on carbon (10 mg), and methanol (1mL) was treated with hydrogen (50 psi) for 24 h on a parr-shakerapparatus, and then the mixture was filtered through a microfilter andwashed with methanol. The filtrate was concentrated and the crudematerial was purified by semi-preparative HPLC to affordN-(1-azabicyclo[2.2.2]oct-3-yl)-2-(2,3-dihydrobenzofuran-5-yl)benzoxazole-4-carboxamide(8 mg, 26%) as a white solid: ¹H NMR (500 MHz, CDCl₃) δ 9.60 (d, J=7.0Hz, 1H), 8.15 (dd, J=7.5, 1.5 Hz, 1H), 8.05 (s, 1H), 8.04 (dd, J=8.5,1.5 Hz, 1H), 7.66 (dd, J=8.5, 1.0 Hz, 1H), 7.42 (t, J=8.0 Hz, 1H), 6.94(d, J=8.5 Hz, 1H), 4.72 (t, J=8.5 Hz, 2H), 4.36-4.30 (m, 1H), 3.54 (ddd,J=14.0, 9.5, 2.0 Hz, 1H), 3.34 (t, J=8.5 Hz, 2H), 3.16-2.86 (m, 5H),2.22-2.09 (m, 2H), 1.83-1.65 (m, 3H); MS (ESI+) m/z 390 (M+H); HPLC >99%(AUC), t_(R)=12.67 min.

Example 65 Preparation ofN-(9-Methyl-9-azabicyclo[3.3.1]non-3-yl)-2-(2,4-dimethoxyphenyl)benzoxazole-4-carboxamide

Step A: To a mixture of 2-amino-3-hydroxybenzoic acid hydrobromide (0.50g, 2.14 mmol) and 2,4-dimethoxybenzoyl chloride (0.43 g, 2.14 mmol) indichloromethane (15 mL) was added triethylamine (1.2 mL, 8.6 mmol)dropwise, then the reaction mixture was stirred at room temperature for12 h. The reaction mixture was diluted with dichloromethane, and thenwashed with 2 N HCl. The aqueous layer was extracted withdichloromethane. The combined organic layers were washed with brine,dried (Na₂SO₄), filtered and concentrated. The crude product wasdissolved in toluene (12 mL) and the solution was treated withp-toluenesulfonic acid monohydrate (348 mg, 1.83 mmol). The reactionmixture was then heated to reflux overnight. The reaction was cooleddown to room temperature, poured into water and extracted with ethylacetate. The organic layer was separated then washed with water, brine,dried (Na₂SO₄), filtered and concentrated. The crude product waspurified by column chromatography (silica gel, 9:1 to 3:1 ethylacetate/methanol) to afford the desired product (0.69 g, quantitative)as a brown solid: ¹H NMR (500 MHz, DMSO-d₆) δ 7.87 (d, J=7.5 Hz, 2H),7.73 (d, J=7.5 Hz, 1H), 7.37 (t, J=7.5 Hz, 1H), 6.70-6.53 (m, 2H), 3.88(s, 3H), 3.82 (s, 3H); MS (ESI+) m/z 300 (M+H).

Step B: A mixture of benzoxazole carboxylic acid from Step A (100 mg,0.33 mmol), 3-amino-9-methyl-9-azabicyclo[3.3.1]nonane dihydrochloride(75 mg, 0.33 mmol), 1-ethyl-3-(3-dimethylaminopropyl)carbodiimidehydrochloride (126 mg, 0.66 mmol) and 1-hydroxybenzotriazole (89 mg,0.66 mmol) in DMF (1.5 mL) was stirred at room temperature for 5 min,then triethylamine (0.18 mL, 1.32 mmol) was added. The resultingreaction mixture was stirred at room temperature for 12 h. The mixturewas diluted with dichloromethane (20 mL), then washed with a saturatedsolution of sodium bicarbonate (10 mL). The aqueous layer was furtherextracted with dichloromethane (3×15 mL). The combined organics weredried (Na₂SO₄), filtered and concentrated. The crude material waspurified by column chromatography (silica gel, 89:10:1dichloromethane/methanol/concentrated ammonium hydroxide) to affordN-(9-methyl-9-azabicyclo[3.3.1]non-3-yl)-2-(2,4-dimethoxyphenyl)benzoxazole-4-carboxamide(80 mg, 56%) as an off-white solid: ¹H NMR (500 MHz, CDCl₃) δ 9.25 (d,J=7.0 Hz, 1H), 8.18-8.13 (m, 2H), 7.65 (dd, J=8.0, 1.0 Hz, 1H), 7.40 (t,J=8.0 Hz, 1H), 6.67 (dd, J=9.0, 2.5 Hz, 1H), 6.62 (d, J=1.0 Hz, 1H),4.64-4.57 (m, 1H), 4.02 (s, 3H), 3.92 (s, 3H), 3.13 (d, J=10.0 Hz, 2H),2.69-2.62 (m, 2H), 2.54 (s, 3H), 2.14-1.97 (m, 3H), 1.62-1.55 (m, 1H),1.49 (t, J=12.0 Hz, 2H), 1.12 (d, J=12.0 Hz, 2H); MS (ESI+) m/z 436(M+H); HPLC 96.6% (AUC), t_(R)=13.35 min.

Example 66 Preparation of(S)-N-(1-Azabicyclo[2.2.2]oct-3-yl)-2-(2,4-dimethoxyphenyl)benzoxazole-4-carboxamide

A mixture of 2-(2,4-dimethoxyphenyl)benzo[d]oxazole-4-carboxylic acid(100 mg, 0.33 mmol), (S)-(−)-3-aminoquinuclidine dihydrochloride (66 mg,0.33 mmol), 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride(126 mg, 0.66 mmol) and 1-hydroxybenzotriazole (89 mg, 0.66 mmol) in DMF(1.5 mL) was stirred at room temperature for 5 min, then triethylamine(0.18 mL, 1.32 mmol) was added. The resulting reaction mixture wasstirred at room temperature for 12 h. The mixture was diluted withdichloromethane (20 mL), then washed with a saturated solution of sodiumbicarbonate (10 mL). The aqueous layer was further extracted withdichloromethane (3×15 mL). The combined organics were dried (Na₂SO₄),filtered and concentrated. The crude material was purified by columnchromatography (silica gel, 89:10:1dichloromethane/methanol/concentrated ammonium hydroxide) to afford(S)-N-(1-azabicyclo[2.2.2]oct-3-yl)-2-(2,4-dimethoxyphenyl)benzoxazole-4-carboxamide(61 mg, 46%) as a white solid: ¹H NMR (500 MHz, CDCl₃) δ 9.68 (d, J=7.0Hz, 1H), 8.16 (d, J=7.5 Hz, 1H), 8.11 (d, J=8.5 Hz, 1H), 7.68 (d, J=8.0Hz, 1H), 7.41 (t, J=8.0 Hz, 1H), 6.68-6.65 (m, 2H), 4.32-4.26 (m, 1H),4.00 (s, 3H), 3.92 (s, 3H), 3.50 (ddd, J=11.5, 9.5, 2.0 Hz, 1H),3.10-2.86 (m, 4H), 2.83 (dd, J=14.5, 4.5 Hz, 1H), 2.22-2.17 (m, 1H),2.10-1.98 (m, 1H), 1.78-1.70 (m, 2H), 1.60-1.51 (m, 1H); MS (ESI+) m/z408 (M+H); HPLC 96.1% (AUC), t_(R)=12.82 min.

Example 67 Preparation ofN-(9-Methyl-9-azabicyclo[3.3.1]non-3-yl)-2-(2,4-dichlorophenyl)benzoxazole-4-carboxamide

Step A: To a mixture of 2-amino-3-hydroxybenzoic acid hydrobromide (0.50g, 2.14 mmol) and 2,4-dichlorobenzoyl chloride (0.30 mL, 2.14 mmol) indichloromethane (15 mL) was added triethylamine (1.2 mL, 8.6 mmol)dropwise, then the reaction mixture was stirred at room temperature for12 h. The reaction mixture was diluted with dichloromethane, and thenwashed with 2 N HCl. The aqueous layer was extracted withdichloromethane. The combined organic layers were washed with brine,dried (Na₂SO₄), filtered and concentrated. The crude product wasdissolved in toluene (13 mL) and the solution was treated withp-toluenesulfonic acid monohydrate (373 mg, 1.96 mmol). The reactionmixture was then heated to reflux overnight. The reaction was cooleddown to room temperature, poured into water and extracted with ethylacetate. The organic layer was separated then washed with water, brine,dried (Na₂SO₄), filtered and concentrated. The crude product waspurified by column chromatography (silica gel, 9:1 to 3:1 ethylacetate/methanol) to afford the desired product (0.34 g, 56%) as anoff-white solid: ¹H NMR (500 MHz, DMSO-d₆) δ 7.92-7.78 (m, 3H),7.65-7.55 (m, 1H), 7.51-7.42 (m, 2H); MS (ESI+) m/z 308 (M+H).

Step B: A mixture of benzoxazole carboxylic acid from Step A (100 mg,0.32 mmol), 3-amino-9-methyl-9-azabicyclo[3.3.1]nonane dihydrochloride(73 mg, 0.32 mmol), 1-ethyl-3-(3-dimethylaminopropyl)carbodiimidehydrochloride (123 mg, 0.64 mmol) and 1-hydroxybenzotriazole (86 mg,0.64 mmol) in DMF (1.5 mL) was stirred at room temperature for 5 min,then triethylamine (0.17 mL, 1.28 mmol) was added. The resultingreaction mixture was stirred at room temperature for 12 h. The mixturewas diluted with dichloromethane (20 mL), then washed with a saturatedsolution of sodium bicarbonate (10 mL). The aqueous layer was furtherextracted with dichloromethane (3×15 mL). The combined organics weredried (Na₂SO₄), filtered and concentrated. The crude material waspurified by column chromatography (silica gel, 89:10:1dichloromethane/methanol/concentrated ammonium hydroxide) to affordN-(9-methyl-9-azabicyclo[3.3.1]non-3-yl)-2-(2,4-dichlorophenyl)benzoxazole-4-carboxamide(63 mg, 44%) as a white solid: ¹H NMR (500 MHz, CDCl₃) δ 9.08 (d, J=7.5Hz, 1H), 8.24 (dd, J=7.5, 1.0 Hz, 1H), 8.20 (d, J=8.5 Hz, 1H), 7.72 (dd,J=8.0, 1.0 Hz, 1H), 7.66 (d, J=2.0 Hz, 1H), 7.52 (t, J=8.0 Hz, 1H), 7.48(dd, J=8.5, 2.0 Hz, 1H), 4.64-4.57 (m, 1H), 3.12 (d, J=10.0 Hz, 2H),2.69-2.62 (m, 2H), 2.53 (s, 3H), 2.14-1.97 (m, 3H), 1.62-1.55 (m, 1H),1.43 (t, J=12.0 Hz, 2H), 1.09 (d, J=12.0 Hz, 2H); MS (ESI+) m/z 444(M+H); HPLC 98.7% (AUC), t_(R)=14.42 min.

Example 68 Preparation of(S)-N-(1-Azabicyclo[2.2.2]oct-3-yl)-2-(2,4-dichlorophenyl)benzoxazole-4-carboxamide

A mixture of 2-(2,4-dichlorophenyl)benzo[d]oxazole-4-carboxylic acid(100 mg, 0.32 mmol), (S)-(−)-3-aminoquinuclidine dihydrochloride (64 mg,0.32 mmol), 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride(123 mg, 0.64 mmol) and 1-hydroxybenzotriazole (86 mg, 0.64 mmol) in DMF(1.5 mL) was stirred at room temperature for 5 min, then triethylamine(0.17 mL, 1.28 mmol) was added. The resulting reaction mixture wasstirred at room temperature for 12 h. The mixture was diluted withdichloromethane (20 mL), then washed with a saturated solution of sodiumbicarbonate (10 mL). The aqueous layer was further extracted withdichloromethane (3×15 mL). The combined organics were dried (Na₂SO₄),filtered and concentrated. The crude material was purified by columnchromatography (silica gel, 89:10:1dichloromethane/methanol/concentrated ammonium hydroxide) to afford(S)-N-(1-azabicyclo[2.2.2]oct-3-yl)-2-(2,4-dichlorophenyl)benzoxazole-4-carboxamide(63 mg, 47%) as a white solid: ¹H NMR (500 MHz, CDCl₃) δ 9.40 (d, J=7.0Hz, 1H), 8.25 (dd, J=7.5, 1.0 Hz, 1H), 8.17 (d, J=8.5 Hz, 1H), 7.75 (dd,J=8.0, 1.0 Hz, 1H), 7.65 (d, J=2.0 Hz, 1H), 7.54 (t, J=8.0 Hz, 1H), 7.47(dd, J=8.5, 2.0 Hz, 1H), 4.32-4.26 (m, 1H), 3.50 (ddd, J=11.5, 9.5, 2.0Hz, 1H), 3.10-2.72 (m, 5H), 2.15-2.10 (m, 1H), 2.02-1.95 (m, 1H),1.82-1.70 (m, 2H), 1.60-1.51 (m, 1H); MS (ESI+) m/z 416 (M+H); HPLC >99%(AUC), t_(R)=13.23 min.

Example 69 Preparation of(S)-N-(1-Azabicyclo[2.2.2]oct-3-yl)-2-(4-chloro-2-methoxyphenyl)benzoxazole-4-carboxamide

Step A: To an ice-cold suspension of 4-chloro-2-methoxybenzoic acid (400mg, 2.14 mmol) in dichloromethane (10 mL) was added oxalyl chloride(0.18 mL, 2.14 mmol) dropwise. After the ice-water bath was removed, themixture was stirred for 1 h. To the above solution was added2-amino-3-hydroxybenzoic acid hydrobromide (0.50 g, 2.14 mmol) followedby the addition of triethylamine (1.19 mL, 8.56 mmol). The resultingreaction mixture was stirred at room temperature overnight. The reactionwas quenched with water (50 mL). The reaction mixture was extracted withdichloromethane. The aqueous layer was extracted with dichloromethane(2×50 mL). The combined organic layers were dried over Na₂SO₄, filtratedand concentrated to afford a yellow solid. The crude was dissolved intoluene (5 mL) and the solution was treated with p-toluenesulfonic acidmonohydrate (258 mg, 1.36 mmol). The reaction mixture was then heated at95° C. under nitrogen for 5 h. The reaction was cooled down to roomtemperature, poured into water and extracted with dichloromethane. Theorganic layer was separated, washed with water, brine, dried overNa₂SO₄, filtered and concentrated to a yellow solid. The crude materialwas purified by recrystallization from methanol to afford the desiredproduct (198 mg, 48%) as an off-white solid: ¹H NMR (500 MHz, DMSO-d₆) δ13.06 (s, 1H), 8.09 (d, J=8.4 Hz, 1H), 8.03 (dd, J=8.1, 0.7 Hz, 1H),7.92 (dd, J=7.8, 0.7 Hz, 1H), 7.52 (t, J=7.9 Hz, 1H), 7.41 (d, J=1.8 Hz,1H), 7.25 (dd, J=8.4, 1.9 Hz, 1H), 3.98 (s, 3H); MS (ESI+) m/z 304(M+H).

Step B: A mixture of2-(4-chloro-2-methoxyphenyl)benzoxazole-4-carboxylic acid (95 mg, 0.31mmol), 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (119mg, 0.62 mmol), 1-hydroxybenzotriazole (76 mg, 0.62 mmol) and(S)-(−)-3-aminoquinuclidine dihydrochloride (78 mg, 0.39 mmol) in DMF (3mL) was stirred at room temperature for 10 min, then triethylamine (0.20mL, 1.4 mmol) was added. The resulting reaction mixture was stirred atroom temperature overnight. The mixture was diluted with dichloromethaneand then washed with a saturated solution of sodium bicarbonate. Theaqueous layer was further extracted with dichloromethane (2×50 mL). Thecombined organic layers were washed with brine (2×50 mL), dried(Na₂SO₄), filtered and concentrated. The crude material was purified bycolumn chromatography (silica gel, 90:9:1dichloromethane/methanol/concentrated ammonium hydroxide) to afford(S)-N-(1-azabicyclo[2.2.2]oct-3-yl)-2-(4-chloro-2-methoxyphenyl)benzoxazole-4-carboxamide(69 mg, 54%) as a white solid: ¹H NMR (500 MHz, CDCl₃) δ 9.59 (d, J=7.0Hz, 1H), 8.19 (dd, J=7.8, 1.0 Hz, 1H), 8.08 (d, J=8.2 Hz, 1H), 7.83 (dd,J=8.2, 1.0 Hz, 1H), 7.47 (t, J=7.9 Hz, 1H), 7.15-7.10 (m, 2H), 4.40-4.22(m, 1H), 4.02 (s, 3H), 3.55-3.50 (m, 1H), 3.20-2.75 (m, 5H), 2.23-2.19(m, 1H), 2.10-2.00 (m, 1H), 1.80-1.75 (m, 2H), 1.60-1.50 (m, 1H); MS(ESI+) m/z 412 (M+H); HPLC >99% (AUC), t_(R)=13.78 min.

Example 70 Preparation ofN-(9-Methyl-9-azabicyclo[3.3.1]non-3-yl)-2-(4-chloro-2-methoxyphenyl)benzoxazole-4-carboxamide

A mixture of 2-(4-chloro-2-methoxyphenyl)benzoxazole-4-carboxylic acid(95 mg, 0.31 mmol), 1-ethyl-3-(3-dimethylaminopropyl)carbodiimidehydrochloride (119 mg, 0.62 mmol), 1-hydroxybenzotriazole (76 mg, 0.62mmol) and 3-amino-9-methyl-9-azabicyclo[3.3.1]nonane dihydrochloride (89mg, 0.39 mmol) in DMF (3 mL) was stirred at room temperature for 10 min,then triethylamine (0.18 mL, 1.25 mmol) was added. The resultingreaction mixture was stirred at room temperature overnight. The mixturewas diluted with dichloromethane and then washed with a saturatedsolution of sodium bicarbonate. The aqueous layer was further extractedwith dichloromethane (3×50 mL). The combined organic layers were washedwith water (3×50 mL), brine (3×50 mL), dried (Na₂SO₄), filtered andconcentrated. The crude material was purified by column chromatography(silica gel, 90:9:1 dichloromethane/methanol/concentrated ammoniumhydroxide) to affordN-(9-methyl-9-azabicyclo[3.3.1]non-3-yl)-2-(4-chloro-2-methoxyphenyl)benzoxazole-4-carboxamide(102 mg, 67%) as a light yellow solid: ¹H NMR (500 MHz, CDCl₃) δ 9.17(br s, 1H), 8.20 (dd, J=7.7, 0.8 Hz, 1H), 8.11 (d, J=8.4 Hz, 1H), 7.69(dd, J=7.3, 0.9 Hz, 1H), 7.45 (t, J=4.0 Hz, 1H), 7.16-7.10 (m, 2H),4.67-4.56 (m, 1H), 4.04 (s, 3H), 3.10-3.02 (m, 2H), 2.70-2.60 (m, 5H),2.57 (s, 3H), 2.20-2.00 (m, 3H), 1.20-1.10 (m, 2H); MS (ESI+) m/z 440(M+H); HPLC 98.7% (AUC), t_(R)=14.10 min.

Example 71 Preparation of(S)-N-(1-Azabicyclo[2.2.2]oct-3-yl)-2-(4-methoxy-2-methylphenyl)benzoxazole-4-carboxamide

Step A: To an ice-cold suspension of 4-methoxy-2-methylbenzoic acid (356mg, 2.14 mmol) in dichloromethane (10 mL) was added oxalyl chloride(0.18 mL, 2.14 mmol) dropwise, then the ice-water bath was removed andthe mixture was stirred for 1 h. To the above solution was added2-amino-3-hydroxybenzoic acid hydrobromide (0.50 g, 2.14 mmol) followedby the addition of triethylamine (1.19 mL, 8.56 mmol). The resultingreaction mixture was stirred at room temperature overnight. The reactionwas quenched with water (50 mL). The reaction mixture was extracted withdichloromethane. The aqueous layer was extracted with dichloromethane(2×50 mL). The combined organic layers were dried over Na₂SO₄, filteredand concentrated to afford a yellow solid. The crude was dissolved intoluene (5 mL) and the solution was treated with p-toluenesulfonic acidmonohydrate (258 mg, 1.36 mmol). The reaction mixture was then heated at95° C. under nitrogen for 5 h. The reaction was cooled down to roomtemperature, poured into water and extracted with dichloromethane. Theorganic layer was separated, washed with water, brine, dried overNa₂SO₄, filtered and concentrated to a yellow solid. The crude productwas purified by column chromatography (silica gel, 9:1 to 3:2 ethylacetate/methanol) to afford the desired product (204 mg, 34%) as ayellow solid: ¹H NMR (500 MHz, DMSO-d₆) δ 13.06 (s, 1H), 8.25-8.10 (m,1H), 7.82-7.75 (m, 2H), 7.37 (t, J=7.9 Hz, 1H), 7.41 (dd, J=8.0, 1.3 Hz,1H), 7.10-6.95 (m, 1H), 3.85 (s, 3H), 3.13 (s, 3H); MS (ESI+) m/z 283(M+H).

Step B: A mixture of2-(4-methoxy-2-methylphenyl)benzoxazole-4-carboxylic acid (100 mg, 0.35mmol), 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (134mg, 0.70 mmol), 1-hydroxybenzotriazole (95 mg, 0.70 mmol) and(S)-(−)-3-aminoquinuclidine dihydrochloride (87 mg, 0.44 mmol) in DMF (3mL) was stirred at room temperature for 10 min, then triethylamine (0.20mL, 1.4 mmol) was added. The resulting reaction mixture was stirred atroom temperature overnight. The mixture was diluted with dichloromethaneand then washed with a saturated solution of sodium bicarbonate. Theaqueous layer was further extracted with dichloromethane (2×50 mL). Thecombined organic layers were washed with brine (2×50 mL), dried(Na₂SO₄), filtered and concentrated. The crude material was purified bycolumn chromatography (silica gel, 90:9:1 ethylacetate/methanol/concentrated ammonium hydroxide) to afford(S)-N-(1-azabicyclo[2.2.2]oct-3-yl)-2-(4-methoxy-2-methylphenyl)benzoxazole-4-carboxamide(41 mg, 30%) as an off-white solid: ¹H NMR (500 MHz, CDCl₃) δ 9.46 (d,J=7.0 Hz, 1H), 8.20-8.15 (m, 2H), 7.72 (dd, J=7.1, 1.0 Hz, 1H), 7.45 (t,J=7.9 Hz, 1H), 6.95-6.90 (m, 2H), 4.51-4.42 (m, 1H), 3.91 (s, 3H),3.70-3.63 (m, 1H), 3.22-3.00 (m, 4H), 2.98-2.90 (m, 1H), 2.86 (s, 3H),2.35-2.30 (m, 1H), 2.20-2.10 (m, 1H), 2.00-1.95 (m, 2H), 1.75-1.70 (m,1H); MS (ESI+) m/z 392 (M+H); HPLC 96.6% (AUC), t_(R)=13.19 min.

Example 72 Preparation ofN-(9-Methyl-9-azabicyclo[3.3.1]non-3-yl)-2-(4-methoxy-2-methylphenyl)benzoxazole-4-carboxamide

A mixture of 2-(4-methoxy-2-methylphenyl)benzoxazole-4-carboxylic acid(100 mg, 0.35 mmol), 1-ethyl-3-(3-dimethylaminopropyl)carbodiimidehydrochloride (134 mg, 0.70 mmol), 1-hydroxybenzotriazole (95 mg, 0.70mmol) and 3-amino-9-methyl-9-azabicyclo[3.3.1]nonane dihydrochloride (99mg, 0.44 mmol) in DMF (3 mL) was stirred at room temperature for 10 min,then triethylamine (0.20 mL, 1.40 mmol) was added. The resultingreaction mixture was stirred at room temperature overnight. The mixturewas diluted with dichloromethane and then washed with a saturatedsolution of sodium bicarbonate. The aqueous layer was further extractedwith dichloromethane (2×50 mL). The combined organic layers were washedwith water (2×50 mL), brine (2×50 mL), dried (Na₂SO₄), filtered andconcentrated. The crude material was purified by column chromatography(silica gel, 90:9:1 dichloromethane/methanol/concentrated ammoniumhydroxide) and recrystallization from acetonitrile to affordN-(9-methyl-9-azabicyclo[3.3.1]non-3-yl)-2-(4-methoxy-2-methylphenyl)benzoxazole-4-carboxamide(24 mg, 16%) as a light yellow solid: ¹H NMR (500 MHz, CDCl₃) δ 9.11 (d,J=7.2 Hz, 1H), 8.22-8.16 (m, 2H), 7.67 (dd, J=8.8, 0.8 Hz, 1H), 7.43 (t,J=7.9 Hz, 1H), 6.94-6.90 (m, 2H), 4.66-4.60 (m, 1H), 3.90 (s, 3H),3.15-3.10 (m, 2H), 2.89 (s, 3H), 2.66-2.58 (m, 2H), 2.55 (s, 3H),2.10-1.90 (m, 3H), 1.58-1.42 (m, 3H), 1.20-1.05 (m, 2H); MS (ESI+) m/z420 (M+H); HPLC >99% (AUC), t_(R)=13.54 min.

Example 73 Preparation of(S)-N-(1-Azabicyclo[2.2.2]oct-3-yl)-2-(4-chloro-2-methylphenyl)benzoxazole-4-carboxamide

Step A: To an ice-cold suspension of 4-chloro-2-methylbenzoic acid (426mg, 2.50 mmol) in dichloromethane (15 mL) was added oxalyl chloride(0.21 mL, 2.50 mmol) dropwise. Then the ice-water bath was removed andthe mixture was stirred for 1 h. To the above solution was added2-amino-3-hydroxybenzoic acid hydrobromide (0.58 g, 2.50 mmol) followedby the addition of triethylamine (1.4 mL, 8.56 mmol). The resultingreaction mixture was stirred at room temperature overnight. The reactionwas quenched with water (50 mL). The reaction mixture was extracted withdichloromethane. The aqueous layer was extracted with dichloromethane(2×50 mL). The combined organic layers were washed with water, brine,dried over Na₂SO₄, flittered and concentrated to afford a yellow solid.The crude was dissolved in toluene (5 mL) and the solution was treatedwith p-toluenesulfonic acid monohydrate (342 mg, 1.80 mmol). Thereaction mixture was then heated at 95° C. under nitrogen for 5 h. Thereaction was cooled down to room temperature, poured into water andextracted with dichloromethane. The organic layer was separated, washedwith water, brine, dried over Na₂SO₄, filtered and concentrated to ayellow solid. The crude material was purified by recrystallization frommethanol to afford the desired product (127 mg, 24%) as a yellow solid:¹H NMR (500 MHz, DMSO-d₆) δ 8.12 (d, J=7.5 Hz, 1H), 7.85-7.80 (m, 2H),7.63-7.60 (m, 1H), 7.45-7.40 (m, 2H); MS (ESI+) m/z 288 (M+H).

Step B: A mixture of 2-(4-chloro-2-methylphenyl)benzoxazole-4-carboxylicacid (59 mg, 0.21 mmol), 1-ethyl-3-(3-dimethylaminopropyl)carbodiimidehydrochloride (79 mg, 0.41 mmol), 1-hydroxybenzotriazole (55 mg, 0.41mmol) and (S)-(−)-3-aminoquinuclidine dihydrochloride (51 mg, 0.26 mmol)in DMF (2 mL) was stirred at room temperature for 10 min, thentriethylamine (0.11 mL, 0.82 mmol) was added. The resulting reactionmixture was stirred at room temperature overnight. The mixture wasdiluted with dichloromethane and then washed with a saturated solutionof sodium bicarbonate. The aqueous layer was further extracted withdichloromethane (2×50 mL). The combined organic layers were washed withbrine (2×50 mL), dried (Na₂SO₄), filtered and concentrated. The crudematerial was purified by preparative TLC (silica gel, 90:9:1dichloromethane/methanol/concentrated ammonium hydroxide) to afford(S)-N-(1-azabicyclo[2.2.2]oct-3-yl)-2-(4-chloro-2-methylphenyl)benzoxazole-4-carboxamide(16 mg, 19%) as a light yellow solid: ¹H NMR (500 MHz, CDCl₃) δ 9.47 (d,J=7.0 Hz, 1H), 8.29 (d, J=1.7 Hz, 1H), 8.20-8.10 (m, 2H), 7.83 (d, J=1.7Hz, 1H), 7.06 (d, J=8.8 Hz, 2H), 4.45-4.35 (m, 1H), 3.93 (s, 3H),3.55-3.45 (m, 1H), 3.15-3.00 (m, 2H), 2.95-2.90 (m, 2H), 2.85-2.75 (m,1H), 2.20-2.15 (m, 1H), 2.10-2.00 (m, 1H), 1.80-1.75 (m, 2H), 1.70-1.55(m, 1H); MS (ESI+) m/z 396 (M+H); HPLC 99.0% (AUC), t_(R)=14.57 min.

Example 74 Preparation ofN-(9-Methyl-9-azabicyclo[3.3.1]non-3-yl)-2-(4-chloro-2-methylphenyl)benzoxazole-4-carboxamide

A mixture of 2-(4-chloro-2-methylphenyl)benzoxazole-4-carboxylic acid(59 mg, 0.21 mmol), 1-ethyl-3-(3-dimethylaminopropyl)carbodiimidehydrochloride (79 mg, 0.41 mmol), 1-hydroxybenzotriazole (55 mg, 0.41mmol) and 3-amino-9-methyl-9-azabicyclo[3.3.1]nonane dihydrochloride (72mg, 0.26 mmol) in DMF (3 mL) was stirred at room temperature for 10 min,then triethylamine (0.11 mL, 0.82 mmol) was added. The resultingreaction mixture was stirred at room temperature overnight. The mixturewas diluted with dichloromethane and then washed with a saturatedsolution of sodium bicarbonate. The aqueous layer was further extractedwith dichloromethane (2×20 mL). The combined organic layers were washedwith water (2×20 mL), brine (2×20 mL), dried (Na₂SO₄), filtered andconcentrated. The crude material was purified by preparative TLC (silicagel, 90:9:1 dichloromethane/methanol/concentrated ammonium hydroxide) toaffordN-(9-methyl-9-azabicyclo[3.3.1]non-3-yl)-2-(4-chloro-2-methylphenyl)benzoxazole-4-carboxamide(19 mg, 22%) as a light yellow solid: ¹H NMR (500 MHz, CDCl₃) δ 9.01 (brs, 1H), 8.22 (dd, J=7.8, 1.0 Hz, 1H), 8.18 (d, J=8.4 Hz, 1H), 7.71 (dd,J=8.1, 0.9 Hz, 1H), 7.49 (t, J=7.9 Hz, 1H), 7.43-7.36 (m, 2H), 4.67-4.60(m, 1H), 3.25-3.15 (m, 2H), 2.88 (s, 3H), 2.70-2.55 (m, 2H), 2.48 (s,3H), 2.10-2.00 (m, 3H), 1.65-1.40 (m, 3H), 1.20-1.10 (m, 2H); MS (ESI+)m/z 424 (M+H); HPLC 98.4% (AUC), t_(R)=13.82 min.

Example 75 Preparation ofN-(9-Methyl-9-azabicyclo[3.3.1]non-3-yl-2-(2,6-dimethylphenyl)benzoxazole-4-carboxamide

Step A: To a solution of 2,6-dimethylbenzoic acid (192 mg, 1.28 mmol) indichloromethane (8 mL) was added oxalyl chloride (0.33 mL, 3.85 mmol)slowly. The reaction was stirred at room temperature for 2 h. Thesolvent was evaporated and the solid was directly redissolved indichloromethane (8 mL). 2-amino-3-hydroxybenzoic acid hydrobromide (314mg, 1.34 mmol) was added, followed by triethylamine (0.75 mL, 5.4 mmol).The resulting reaction mixture was stirred at room temperatureovernight. The reaction was quenched with aqueous 2 N HCl (25 mL) untilthe solution reached pH 1. The aqueous layer was extracted withdichloromethane. The organic layers were washed with brine and driedover Na₂SO₄, filtered and concentrated. The residue was directlyre-dissolved in toluene (7 mL) and the solution was treated withp-toluenesulfonic acid monohydrate (312 mg, 1.64 mmol). The reactionmixture was then heated to reflux for 1.5 h. The reaction was cooleddown to room temperature and the toluene was evaporated. The reactionmixture was poured into water and extracted with ethyl acetate. Theorganic layer was separated, then washed with water, brine, dried overNa₂SO₄, filtered and concentrated to a yellow solid. The crude productwas purified by column chromatography (silica gel, 9:1 to 2:1 ethylacetate/methanol) to afford the desired product (101 mg, 35%) as ayellow solid: ¹H NMR (500 MHz, CD₃OD) δ 7.95-7.86 (m, 1H), 7.79 (d,J=8.0 Hz, 1H), 7.48 (t, J=7.5 Hz, 1H), 7.30-7.24 (m, 1H), 7.14-6.98 (m,2H), 3.34 (s, 3H), 3.31 (s, 3H); MS (ESI+) m/z 268 (M+H).

Step B: A mixture of 2-(2,6-dimethylphenyl)benzoxazole-4-carboxylic acidfrom Step A (44 mg, 0.17 mmol),3-amino-9-methyl-9-azabicyclo[3.3.1]nonane dihydrochloride (45 mg, 0.20mmol), 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (65mg, 0.34 mmol) and 1-hydroxybenzotriazole (46 mg, 0.34 mmol) in DMF (2mL) was stirred at room temperature for 10 min, then triethylamine (0.12mL, 0.85 mmol) was added. The resulting reaction mixture was stirred atroom temperature overnight. The mixture was diluted with dichoromethane(30 mL), and then washed with a saturated solution of sodiumbicarbonate. The aqueous layer was further extracted withdichloromethane (2×30 mL). The combined organics were dried (Na₂SO₄),filtered and concentrated. The crude material was purified by columnchromatography (silica gel, 90:9:1 ethyl acetate/methanol/concentratedammonium hydroxide) and semi-preparative HPLC to affordN-(9-methyl-9-azabicyclo[3.3.1]non-3-yl-2-(2,6-dimethylphenyl)benzoxazole-4-carboxamide(11 mg, 16%) as an off-white solid: ¹H NMR (500 MHz, CDCl₃) δ 8.99 (s,1H), 8.25 (d, J=7.5 Hz, 1H), 7.72 (d, J=8.0 Hz, 1H), 7.50 (t, J=8.0 Hz,1H), 7.38 (t, J=7.5 Hz, 1H), 7.22 (d, J=8.0 Hz, 2H), 4.63-4.56 (m, 1H),3.18-3.11 (m, 2H), 2.63-2.53 (m, 5H), 2.41 (s, 6H), 2.10-1.92 (m, 3H),1.56-1.38 (m, 3H), 1.18-1.02 (m, 2H); MS (ESI+) m/z 404 (M+H); HPLC >99%(AUC), t_(R)=13.13 min.

Example 76 Preparation of(S)-N-(1-Azabicyclo[2.2.2]oct-3-yl)-2-(2,6-dichlorophenyl)benzoxazole-4-carboxamide

Step A: To a suspension of 2-amino-3-hydroxybenzoic acid hydrobromide(350 mg, 1.50 mmol) in dichloromethane (8 mL) was added2,6-dichlorobenzoyl chloride (0.21 mL, 1.50 mmol). The resultingreaction mixture was stirred at room temperature for 10 min, thentriethylamine (0.83 mL, 6.00 mmol) was added and the reaction mixturewas stirred at room temperature overnight. The reaction was diluted indichloromethane (30 mL) and quenched with aqueous 2 N HCl (10 mL) untilthe solution reached pH 1. The aqueous layer was further extracted withdichloromethane (2×30 mL). The organic layers were washed with water andbrine, dried over Na₂SO₄, filtered and concentrated. The residue wasdirectly re-dissolved in toluene (8 mL) and the solution was treatedwith p-toluenesulfonic acid monohydrate (253 mg, 1.33 mmol). Thereaction mixture was then heated to reflux overnight. The reaction wascooled down to room temperature and the toluene was evaporated. Thereaction mixture was poured into water and extracted with ethyl acetate.The organic layer was separated, then washed with water, brine, driedover Na₂SO₄, filtered and concentrated to an orange solid. The crudeproduct was purified by column chromatography (silica gel, 9:1 to 3:1ethyl acetate/methanol) to afford the desired product (194 mg, 70%) as apale orange solid: ¹H NMR (300 MHz, DMSO-d₆) δ 7.87-7.38 (m, 6H); MS(ESI+) m/z 308 (M+H).

Step B: A mixture of 2-(2,6-dichlorophenyl)benzoxazole-4-carboxylic acidfrom Step A (73 mg, 0.24 mmol), (S)-3-aminoquinuclidine dihydrochloride(58 mg, 0.29 mmol), 1-ethyl-3-(3-dimethylaminopropyl)carbodiimidehydrochloride (92 mg, 0.48 mmol) and 1-hydroxybenzotriazole (65 mg, 0.48mmol) in DMF (2.5 mL) was stirred at room temperature for 10 min, thentriethylamine (0.17 mL, 1.20 mmol) was added. The resulting reactionmixture was stirred at room temperature overnight. The mixture wasdiluted with dichloromethane (30 mL), and then washed with a saturatedsolution of sodium bicarbonate. The aqueous layer was further extractedwith dichloromethane (2×30 mL). The combined organics were dried(Na₂SO₄), filtered and concentrated. The crude material was purified bycolumn chromatography (silica gel, 90:9:1 ethylacetate/methanol/concentrated ammonium hydroxide) and recrystallizationfrom acetonitrile to afford(S)-N-(1-azabicyclo[2.2.2]oct-3-yl)-2-(2,6-dichlorophenyl)benzoxazole-4-carboxamide(31 mg, 31%) as white needles: ¹H NMR (500 MHz, CDCl₃) δ 9.38 (d, J=6.5Hz, 1H), 8.27 (d, J=7.5 Hz, 1H), 7.78 (d, J=8.0 Hz, 1H), 7.59-7.46 (m,4H), 4.33-4.25 (m, 1H), 3.47 (t, J=11.0 Hz, 1H), 3.02-2.85 (m, 4H),2.81-2.74 (m, 1H), 2.11 (s, 1H), 1.99-1.90 (m, 1H), 1.78-1.69 (m, 2H),1.56-1.46 (m, 1H); MS (ESI+) m/z 416 (M+H); HPLC >99% (AUC), t_(R)=12.19min.

Example 77 Preparation ofN-(9-Methyl-9-azabicyclo[3.3.1]non-3-yl)-2-(2,6-dichlorophenyl)benzoxazole-4-carboxamide

A mixture of 2-(2,6-dichlorophenyl)benzoxazole-4-carboxylic acid (71 mg,0.23 mmol), 3-amino-9-methyl-9-azabicyclo[3.3.1]nonane dihydrochloride(64 mg, 0.28 mmol), 1-ethyl-3-(3-dimethylaminopropyl)carbodiimidehydrochloride (88 mg, 0.46 mmol) and 1-hydroxybenzotriazole (62 mg, 0.46mmol) in DMF (2 mL) was stirred at room temperature for 10 min, thentriethylamine (0.16 mL, 1.16 mmol) was added. The resulting reactionmixture was stirred at room temperature overnight. The mixture wasdiluted with dichloromethane (30 mL), and then washed with a saturatedsolution of sodium bicarbonate (10 mL). The aqueous layer was furtherextracted with dichloromethane (2×30 mL). The combined organics weredried (Na₂SO₄), filtered and concentrated. The crude material waspurified by column chromatography (silica gel, 90:9:1 ethylacetate/methanol/concentrated ammonium hydroxide) and recrystallizationfrom acetonitrile to affordN-(9-methyl-9-azabicyclo[3.3.1]non-3-yl)-2-(2,6-dichlorophenyl)benzoxazole-4-carboxamide(39 mg, 38%) as off-white crystals: ¹H NMR (500 MHz, CDCl₃) δ 8.85 (s,1H), 8.29 (d, J=7.5 Hz, 1H), 7.76 (d, J=7.5 Hz, 1H), 7.57-7.46 (m, 4H),4.62-4.54 (m, 1H), 3.14-3.06 (m, 2H), 2.53 (s, 3H), 2.05-1.92 (m, 3H),1.65-1.40 (m, 5H), 1.16-1.05 (m, 2H); MS (ESI+) m/z 444 (M+H); HPLC >99%(AUC), t_(R)=12.70 min.

Example 78 Preparation ofN-(1-Azabicyclo[2.2.2]oct-3-yl)-6-chloro-2-p-tolylbenzoxazole-4-carboxamide

Step A: To a 60 mL of aqueous solution of KOH (2.68 g, 47.8 mmol) wasadded ether (200 mL) followed by the addition of1-methyl-3-nitro-1-nitrosoguanidine (5.28 g, 35.9 mmol) slowly at 0° C.The ethereal layer was isolated and added into a solution of2-amino-3-methoxybenzoic acid (2.0 g, 11.9 mmol) in acetone (20 mL). Thereaction mixture was quenched with 2 mL of acetic acid and concentratedunder reduced pressure. The residue was dissolved into ether and washedwith saturated solution of NaHCO₃, brine, dried over Na₂SO₄, filteredand concentrated to a light orange solid (2.16 g, 99%): ¹H NMR (300 MHz,CDCl₃) δ 7.47 (dd, J=8.2, 1.0 Hz, 1H), 6.85 (dd, J=7.8, 1.2 Hz, 1H),6.58 (t, J=8.4 Hz, 1H), 6.00 (br s, 2H), 3.87 (s, 6H).

Step B: To a solution of methyl ester from Step A (2.16 g, 11.9 mmol) inDMF (15 mL) was added N-chlorosuccinimide (1.60 g, 11.9 mmol). Theresulting mixture was stirred and heated at 50° C. for 2 h. The reactionmixture was cooled to room temperature, then diluted with ether andwater. The aqueous layer was isolated and extracted with ether (2×100mL). The combined organic layers were washed with water (2×100 mL),brine (100 mL), dried over Na₂SO₄, filtered and concentrated to afford2-amino-5-chloro-3-methoxybenzoate (2.36 g, 92%) as a brown solid: ¹HNMR (300 MHz, CDCl₃) δ 7.45 (d, J=2.2 Hz, 1H), 6.79 (d, J=2.2 Hz, 1H),6.00 (br s, 2H), 3.87 (s, 6H).

Step C: A mixture of 2-amino-5-chloro-3-methoxybenzoate (2.76 g, 12.8mmol), 48% aqueous solution of hydrobromic acid (25 mL) and glacialacetic acid (1 mL) was heated to reflux for 48 h. The reaction mixturewas cooled down to room temperature, treated with saturated solution ofNa₂CO₃ to pH˜6, concentrated and purified by column chromatography(silica gel, 90:10 dichloromethane/methanol) to afford2-amino-5-chloro-3-hydroxybenzoic acid (0.84 g, 35%) as a light brownsolid: MS (ESI+) m/z 188 (M+H).

Step D: To a suspension of 2-amino-5-chloro-3-hydroxybenzoic acid (100mg, 0.53 mmol) in dichloromethane (10 mL) was added pyridine (0.17 mL,2.13 mmol) followed by p-tolyl chloride (246 mg, 1.6 mmol) at roomtemperature. The resulting reaction mixture was stirred at roomtemperature for 20 min, then DMAP (7 mg, 0.05 mmol) was added. Thereaction mixture was stirred at room temperature overnight, thenquenched with aqueous 2 N HCl (50 mL). The reaction was extracted withethyl acetate, then the organic layer was washed with brine, dried overNa₂SO₄, filtered and concentrated to a yellow solid. The crude wasdissolved in toluene (10 mL) and the solution was treated withp-toluenesulfonic acid monohydrate (146 mg, 0.77 mmol). The reactionmixture was then heated to reflux under nitrogen overnight. The reactionwas cooled down to room temperature, poured into water and extractedwith ethyl acetate. The organic layer was separated then washed withwater, brine, dried over Na₂SO₄, filtered and concentrated to give ayellow solid. The crude product was purified by column chromatography(silica gel, 9:1 to 3:1, ethyl acetate/methanol) to afford the desiredproduct (90 mg, 60%) as a yellow solid: MS (ESI+) m/z 288 (M+H).

Step E: A mixture of 6-chloro-2-p-tolylbenzoxazole-4-carboxylic acidfrom Step D (45 mg, 0.16 mmol),1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (60 mg, 0.31mmol), 1-hydroxybenzotriazole (43 mg, 0.31 mmol) and 3-aminoquinuclidinedihydrochloride (37 mg, 0.19 mmol) in DMF (5 mL) was stirred 10 min atroom temperature, then triethylamine (0.07 mL, 0.63 mmol) was added tothe reaction mixture. The resulting reaction mixture was stirred at roomtemperature for 12 h. The mixture was diluted with ethyl acetate (20mL), and then washed with a saturated solution of sodium bicarbonate.The aqueous layer was further extracted with ethyl acetate (2×25 mL).The combined organics were dried (Na₂SO₄), filtered and concentrated.The crude material was purified by column chromatography (silica gel,90:9:1 ethyl acetate/methanol/concentrated ammonium hydroxide) to affordN-(1-azabicyclo[2.2.2]oct-3-yl)-6-chloro-2-p-tolylbenzoxazole-4-carboxamide(18 mg, 29%) as a white solid: ¹H NMR (500 MHz, CDCl₃) δ 9.48 (d, J=7.3Hz, 1H), 8.16 (d, J=1.9 Hz, 1H), 8.10 (d, J=8.2 Hz, 2H), 7.69 (d, J=1.9Hz, 1H), 7.37 (d, J=8.0 Hz, 2H), 4.32-4.25 (m, 1H), 3.55-3.45 (m, 1H),3.12-3.00 (m, 2H), 2.95-2.85 (m, 2H), 2.82 (dd, J=14.3, 3.8 Hz, 1H),2.48 (s, 3H), 2.20-2.00 (m, 2H), 1.80-1.70 (m, 3H); MS (ESI+) m/z 396(M+H); HPLC >99% (AUC), t_(R)=13.30 min.

Example 79 Preparation ofN-(9-Methyl-9-azabicyclo[3.3.1]non-3-yl)-6-chloro-2-p-tolylbenzoxazole-4-carboxamide

A mixture of 6-chloro-2-p-tolylbenzoxazole-4-carboxylic acid (45 mg,0.16 mmol), 3-amino-9-methyl-9-azabicyclo[3.3.1]nonane dihydrochloride(43 mg, 0.19 mmol), 1-ethyl-3-(3-dimethylaminopropyl)carbodiimidehydrochloride (60 mg, 0.31 mmol) and 1-hydroxybenzotriazole (43 mg, 0.31mmol) in DMF (5 mL) was stirred for 10 min at room temperature, thentriethylamine (0.07 mL, 0.63 mmol) was added. The resulting reactionmixture was stirred at room temperature for 12 h. The mixture wasdiluted with ethyl acetate (20 mL), and then washed with a saturatedsolution of sodium bicarbonate. The aqueous layer was further extractedwith ethyl acetate (2×22 mL). The combined organics were dried (Na₂SO₄),filtered and concentrated. The crude material was purified by columnchromatography (silica gel, 90:9:1 ethyl acetate/methanol/concentratedammonium hydroxide) to affordN-(9-methyl-9-azabicyclo[3.3.1]non-3-yl)-6-chloro-2-p-tolylbenzoxazole-4-carboxamide(18 mg, 26%) as a white solid: ¹H NMR (500 MHz, CDCl₃) δ 8.94 (d, J=7.3Hz, 1H), 8.18 (d, J=1.9 Hz, 1H), 8.11 (d, J=8.2 Hz, 2H), 7.67 (d, J=1.9Hz, 1H), 7.39 (d, J=8.0 Hz, 2H), 4.63-4.50 (m, 1H), 3.12 (d, J=10.4 Hz,2H), 2.70-2.57 (m, 2H), 2.54 (s, 3H), 2.48 (s, 3H), 2.20-1.90 (m, 2H),1.65-1.52 (m, 2H), 1.51-1.48 (m, 2H), 1.20-1.10 (m, 2H); MS (ESI+) m/z424 (M+H); HPLC 95.0% (AUC), t_(R)=13.80 min.

Example 80 Preparation ofN-(1-Azabicyclo[2.2.2]oct-3-yl)-6-chloro-2-(4-methoxyphenyl)benzoxazole-4-carboxamide

Step A: To a suspension of 2-amino-5-chloro-3-hydroxybenzoic acid (200mg, 1.07 mmol) in dichloromethane (20 mL) was added pyridine (0.35 mL,4.28 mmol) followed by p-anisoyl chloride (548 mg, 3.21 mmol) at roomtemperature. The resulting reaction mixture was stirred at roomtemperature for 20 min, then DMAP (13 mg, 0.10 mmol) was added and thereaction mixture was stirred at room temperature overnight. The reactionwas quenched with aqueous 2 N HCl (50 mL). The reaction mixture wasextracted with ethyl acetate, and the organic layer was washed withbrine, dried over Na₂SO₄, filtered and concentrated to give a yellowsolid. The crude was dissolved in toluene (10 mL) and the solutiontreated with p-toluenesulfonic acid monohydrate (319 mg, 1.68 mmol). Thereaction mixture was then heated to reflux under nitrogen overnight. Thereaction was cooled down to room temperature, poured into water andextracted with ethyl acetate. The organic layer was separated thenwashed with water, brine, dried over Na₂SO₄, filtered and concentratedto a yellow solid. The crude product was purified by columnchromatography (silica gel, 9:1 to 3:1 ethyl acetate/methanol) to affordthe desired product (89 mg, 26%) as an off-white solid: MS (ESI+) m/z304 (M+H).

Step B: A mixture of6-chloro-2-(4-methoxyphenyl)-benzoxazole-4-carboxylic acid from Step A(42 mg, 0.14 mmol), 1-ethyl-3-(3-dimethylaminopropyl)carbodiimidehydrochloride (53 mg, 0.28 mmol), 1-hydroxybenzotriazole (37 mg, 0.28mmol) and 3-aminoquinuclidine dihydrochloride (33 mg, 0.17 mmol) in DMF(4 mL) was stirred for 10 min at room temperature, then triethylamine(0.08 mL, 0.55 mmol) was added. The resulting reaction mixture wasstirred at room temperature for 12 h. The mixture was diluted with ethylacetate and then washed with a saturated solution of sodium bicarbonate.The aqueous layer was further extracted with ethyl acetate (2×50 mL).The combined organic layers were dried (Na₂SO₄), filtered andconcentrated. The crude material was purified by column chromatography(silica gel, 90:9:1 ethyl acetate/methanol/concentrated ammoniumhydroxide) to affordN-(1-azabicyclo[2.2.2]oct-3-yl)-6-chloro-2-(4-methoxyphenyl)benzoxazole-4-carboxamide(14 mg, 25%) as a white solid: ¹H NMR (500 MHz, CDCl₃) δ 9.48 (d, J=7.3Hz, 1H), 8.18-8.10 (m, 3H), 7.68 (d, J=1.9 Hz, 1H), 7.07 (d, J=8.9 Hz,2H), 4.40-4.32 (m, 1H), 3.93 (s, 3H), 3.60-3.50 (m, 1H), 3.20-3.05 (m,2H), 3.00-2.95 (m, 2H), 2.87 (dd, J=14.1, 3.5 Hz, 1H), 2.20 (q, J=3.1Hz, 1H), 215-2.00 (m, 1H), 1.85-1.80 (m, 2H), 1.74-1.57(m, 1H); MS(ESI+) m/z 412 (M+H); HPLC >99% (AUC), t_(R)=13.09 min.

Example 81 Preparation ofN-(9-Methyl-9-azabicyclo[3.3.1]non-3-yl)-6-chloro-2-(4-methoxyphenyl)benzoxazole-4-carboxamide

A mixture of 6-chloro-2-(4-methoxyphenyl)benzoxazole carboxylic acid (42mg, 0.14 mmol), 1-ethyl-3-(3-dimethylaminopropyl)carbodiimidehydrochloride (60 mg, 0.31 mmol), 1-hydroxybenzotriazole (43 mg, 0.31mmol) and 3-amino-9-methyl-9-azabicyclo[3.3.1]nonane dihydrochloride (43mg, 0.19 mmol) in DMF (4 mL) was stirred for 10 min at room temperature,then triethylamine (0.08 mL, 0.55 mmol) was added. The resultingreaction mixture was stirred at room temperature for 18 h. The mixturewas diluted with ethyl acetate and then washed with a saturated solutionof sodium bicarbonate. The aqueous layer was further extracted withethyl acetate (2×50 mL). The combined organic layers were washed withbrine, dried (Na₂SO₄), filtered and concentrated. The crude material waspurified by preparative TLC (silica gel, 90:9:1 ethylacetate/methanol/concentrated ammonium hydroxide) to affordN-(9-methyl-9-azabicyclo[3.3.1]non-3-yl)-6-chloro-2-(4-methoxyphenyl)benzoxazole-4-carboxamide(11 mg, 18%) as a white solid: ¹H NMR (500 MHz, CDCl₃) δ 8.98 (br s,1H), 8.20-8.15 (m, 3H), 7.66 (d, J=1.8 Hz, 1H), 7.08 (d, J=8.7 Hz, 2H),4.60-4.45 (m, 1H), 3.93 (s, 3H), 3.35-3.05 (m, 2H), 2.70-2.50 (m, 6H),2.20-1.90 (m, 3H), 1.70-1.45 (m, 3H), 1.35-1.10 (m, 1H); MS (ESI+) m/z440 (M+H); HPLC 97.8% (AUC), t_(R)=13.65 min.

Example 82 Preparation ofN-(1-Azabicyclo[2.2.2]oct-3-yl)-6-bromo-2-phenylbenzoxazole-4-carboxamide

Step A: To a solution of 2-amino-3-methoxybenzoate (1.62 g, 8.97 mmol)in DMF (15 mL) was added N-bromosuccinimide (1.76 g, 9.87 mmol). Theresulting mixture was stirred at room temperature for 2 h. The reactionmixture was diluted with ether and water. The aqueous layer was isolatedand extracted with ether (2×100 mL). The combined organic layers werewashed with water (2×100 mL), brine, dried over Na₂SO₄, filtered andconcentrated to afford a brown solid. The crude material was purified bycolumn chromatography (silica gel, 95:5 hexanes/ethyl acetate) to affordthe desired product (2.08 g, 89%) as a light orange solid: ¹H NMR (300MHz, CDCl₃) δ 7.60 (d, J=2.1 Hz, 1H), 6.90 (d, J=2.1 Hz, 1H), 6.03 (brs, 2H), 3.86 (s, 6H); MS (ESI+) m/z 259 (M+H).

Step B: A mixture of 2-amino-5-bromo-3-methoxybenzoate (2.08 g, 8.03mmol), 48% aqueous solution of hydrobromic acid (20 mL) and glacialacetic acid (0.75 mL) was heated to reflux for 18 h. The reactionmixture was cooled down to room temperature. A light brown solid wasprecipitated and the solid was filtered, washed with diethyl ether andhexanes to afford the desired compound (0.92 g, 51%) as a light brownsolid: MS (ESI+) m/z 232 (M+H).

Step C: To a suspension of 2-amino-5-bromo-3-hydroxybenzoic acidhydrobromide (312 mg, 1.0 mmol) in dichloromethane (10 mL) was addedpyridine (0.49 mL, 6.0 mmol) followed by benzoyl chloride (420 mg, 3.0mmol) at room temperature. The resulting reaction mixture was stirred atroom temperature for 20 min then DMAP (24 mg, 0.20 mmol) was added, andthe reaction mixture was stirred room temperature overnight. Thereaction was quenched with aqueous 2 N HCl (50 mL), then extracted withdichloromethane (2×100 mL). The combined organic layers were dried overNa₂SO₄, filtered and concentrated to a yellow solid. The crude wasdissolved in toluene (10 mL) and the solution was treated withp-toluenesulfonic acid monohydrate (350 mg, 1.84 mmol). The reactionmixture was then heated to reflux under nitrogen for 22 h. The reactionwas cooled down to room temperature, poured into water and extractedwith ethyl acetate. The organic layer was separated then washed withwater, brine, dried over Na₂SO₄, filtered and concentrated to a yellowsolid. The crude product was purified by column chromatography (silicagel, 9:1 to 3:1 ethyl acetate/methanol) to afford the desired product(169 mg, 43%) as a yellow solid: MS (ESI+) m/z 317 (M+H).

Step D: A mixture of 6-bromo-2-phenylbenzoxazole-4-carboxylic acid fromStep C (82 mg, 0.26 mmol), 1-ethyl-3-(3-dimethylaminopropyl)carbodiimidehydrochloride (99 mg, 0.52 mmol), 1-hydroxybenzotriazole (70 mg, 0.52mmol) and 3-aminoquinuclidine dihydrochloride (62 mg, 0.31 mmol) in DMF(5 mL) was stirred for 10 min at room temperature, then triethylamine(0.10 mL, 1.03 mmol) was added. The resulting reaction mixture wasstirred at room temperature for 12 h. The mixture was diluted with ethylacetate (50 mL), and then washed with a saturated solution of sodiumbicarbonate. The aqueous layer was further extracted with ethyl acetate(2×50 mL). The combined organics were dried (Na₂SO₄), filtered andconcentrated. The crude material was purified by column chromatography(silica gel, 90:9:1 ethyl acetate/methanol/concentrated ammoniumhydroxide) to affordN-(1-azabicyclo[2.2.2]oct-3-yl)-6-bromo-2-phenylbenzoxazole-4-carboxamide(61 mg, 55%) as a white solid: ¹H NMR (500 MHz, CDCl₃) δ 9.45 (d, J=7.3Hz, 1H), 8.32 (d, J=1.9 Hz, 1H), 8.25-8.15 (m, 2H), 7.89 (d, J=1.8 Hz,1H), 7.65-7.52 (m, 3H), 4.40-4.25 (m, 1H), 3.60-3.45 (m, 1H), 3.18-3.12(m, 2H), 2.90-2.80 (m, 2H), 2.83 (dd, J=14.3, 3.9 Hz, 1H), 2.22-2.15 (m,1H), 2.10-2.00 (m, 2H), 1.85-1.60 (m, 2H); MS (ESI+) m/z 426 (M+H); HPLC98.1% (AUC), t_(R)=12.98 min.

Example 83 Preparation ofN-(9-Methyl-9-azabicyclo[3.3.1]non-3-yl)-6-bromo-2-phenylbenzoxazole-4-carboxamide

A mixture of 6-bromo-2-phenylbenzoxazole-4-carboxylic acid (82 mg, 0.26mmol), 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (99mg, 0.52 mmol), 1-hydroxybenzotriazole (70 mg, 0.52 mmol) and3-amino-9-methyl-9-azabicyclo[3.3.1]nonane (48 mg, 0.31 mmol) in DMF (5mL) was stirred 10 min at room temperature, then triethylamine (0.10 mL,1.03 mmol) was added. The resulting reaction mixture was stirred at roomtemperature overnight. The mixture was diluted with diethyl ether (50mL) and then washed with a saturated solution of sodium bicarbonate. Theaqueous layer was further extracted with ethyl acetate (2×50 mL). Thecombined organics were dried (Na₂SO₄), filtered and concentrated underreduced pressure. During the concentration, a white solid was crashedout. The solid was isolated, washed with ether and dried under highvacuum to affordN-(9-methyl-9-azabicyclo[3.3.1]non-3-yl)-6-bromo-2-phenylbenzoxazole-4-carboxamide(40 mg, 34%) as a white solid: ¹H NMR (500 MHz, CDCl₃) δ 8.89 (d, J=7.3Hz, 1H), 8.34 (d, J=1.8 Hz, 1H), 8.25-8.20 (m, 2H), 7.86 (d, J=1.8 Hz,1H), 7.65-7.55 (m, 3H), 4.60-4.52 (m, 1H), 3.12 (d, J=10.8 Hz, 2H),2.70-2.60 (m, 2H), 2.54 (s, 3H), 2.20-1.95 (m, 2H), 1.62-1.52 (m, 2H),1.50-1.45 (m, 2H), 1.20-1.10 (m, 2H); MS (ESI+) m/z 454 (M+H); HPLC >99%(AUC), t_(R)=13.52 min.

Example 84 Preparation ofN-(1-Azabicyclo[2.2.2]oct-3-yl)-6-bromo-2-p-tolylbenzoxazole-4-carboxamide

Step A: To a suspension of 2-amino-5-bromo-3-hydroxybenzoic acidhydrobromide (290 mg, 0.93 mmol) in dichloromethane (10 mL) was addedpyridine (0.46 mL, 5.60 mmol) followed by p-tolyl chloride (431 mg, 2.80mmol) at room temperature. The resulting reaction mixture was stirred atroom temperature for 20 min and then DMAP (22 mg, 0.19 mmol) was addedto the reaction mixture. The resulting reaction mixture was stirred atroom temperature overnight. The reaction was quenched with water (50mL), then extracted with dichloromethane (2×50 mL). The combined organiclayers were dried over Na₂SO₄, filtrated and concentrated to afforded apinkish solid, which was dissolved in toluene (10 mL) and the solutiontreated with p-toluenesulfonic acid monohydrate (333 mg, 1.76 mmol). Thereaction mixture was then heated to reflux under nitrogen for 22 h. Thereaction was cooled down to room temperature, poured into water andextracted with ethyl acetate. The organic layer was separated, washedwith water, brine, dried over Na₂SO₄, filtered and concentrated to ayellow solid. The crude product was purified by column chromatography(silica gel, 9:1 to 3:1 ethyl acetate/methanol) to afford the desiredproduct (173 mg, 56%) as a yellow solid: MS (ESI+) m/z 332 (M+H).

Step B: A mixture of 6-bromo-2-p-tolylbenzoxazole-4-carboxylic acid (85mg, 0.26 mmol), 1-ethyl-3-(3-dimethylaminopropyl)carbodiimidehydrochloride (60 mg, 0.31 mmol), 1-hydroxybenzotriazole (60 mg, 0.31mmol) and 3-aminoquinuclidine dihydrochloride (61 mg, 0.31 mmol) in DMF(5 mL) was stirred 10 min at room temperature, then triethylamine (0.12mL, 1.02 mmol) was added. The resulting reaction mixture was stirred atroom temperature overnight. The mixture was diluted with ethyl acetate(20 mL), and then washed with a saturated solution of sodiumbicarbonate. The aqueous layer was further extracted with ethyl acetate(2×25 mL). The combined organic layers were dried (Na₂SO₄), filtered andconcentrated under reduced pressure. The crude material was purified bycolumn chromatography (silica gel, 90:9:1 ethylacetate/methanol/concentrated ammonium hydroxide) to affordN-(1-azabicyclo[2.2.2]oct-3-yl)-6-bromo-2-p-tolylbenzoxazole-4-carboxamide(60 mg, 54%) as a white solid: ¹H NMR (500 MHz, CDCl₃) δ 9.48 (d, J=7.3Hz, 1H), 8.30 (d, J=1.8 Hz, 1H), 8.10 (d, J=8.3 Hz, 2H), 7.85 (d, J=1.8Hz, 1H), 7.37 (d, J=8.0 Hz, 2H), 4.35-4.25 (m, 1H), 3.60-3.45 (m, 1H),3.15-3.00 (m, 2H), 2.95-2.82 (m, 2H),

2.80 (dd, J=14.2, 4.1 Hz, 1H), 2.48 (s, 3H), 2.14 (q, J=3.1 Hz, 1H),2.10-2.00 (m, 1H), 1.80-1.60 (m, 3H); MS (ESI+) m/z 440 (M+H); HPLC98.6% (AUC), t_(R)=13.51 min.

Example 85 Preparation ofN-(9-Methyl-9-azabicyclo[3.3.1]non-3-yl)-6-bromo-2-p-tolylbenzoxazole-4-carboxamide

Step A: To a suspension of 2-amino-5-bromo-3-hydroxybenzoic acidhydrobromide (290 mg, 0.93 mmol) in dichloromethane (10 mL) was addedpyridine (0.46 mL, 5.60 mmol) followed by p-toluoyl chloride (431 mg,2.80 mmol) at room temperature. The resulting reaction mixture wasstirred at room temperature for 20 min and then DMAP (22 mg, 0.19 mmol)was added to the reaction mixture. The resulting reaction mixture wasstirred at room temperature overnight. The reaction was quenched withwater (50 mL). The organic layer was separated and the aqueous layer wasextracted with dichloromethane (2×50 mL). The combined organic layerswere dried over Na₂SO₄, filtrated and concentrated to afford a pinkishsolid. The crude was dissolved in toluene (10 mL) and the solution wastreated with p-toluenesulfonic acid monohydrate (333 mg, 1.76 mmol). Thereaction mixture was then heated to reflux under nitrogen for 22 h. Thereaction was cooled down to room temperature, poured into water andextracted with ethyl acetate. The combined organic layers were washedwith water, brine, dried over Na₂SO₄, filtered and concentrated to ayellow solid. The crude product was purified by column chromatography(silica gel, 9:1 to 3:1 ethyl acetate/methanol) to afford the desiredproduct (173 mg, 56%) as a yellow solid: MS (ESI+) m/z 332 (M+H).

Step B: A mixture of 6-bromo-2-p-tolylbenzoxazole-4-carboxylic acid (85mg, 0.26 mmol), 3-amino-9-methyl-9-azabicyclo[3.3.1]nonanedihydrochloride (85 mg, 0.31 mmol), 1-hydroxybenzotriazole (69 mg, 0.51mmol) and 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride(98 mg, 0.51 mmol) in DMF (5 mL) was stirred for 10 min at roomtemperature, then triethylamine (0.12 mL, 1.02 mmol) was added. Theresulting reaction mixture was stirred at room temperature overnight.The mixture was diluted with ethyl acetate (20 mL), and then washed witha saturated solution of sodium bicarbonate. The aqueous layer wasfurther extracted with ethyl acetate (2×50 mL). The combined organiclayers were dried (Na₂SO₄), filtered and concentrated under reducedpressure. The crude material was purified by column chromatography(silica gel, 90:9:1 ethyl acetate/methanol/concentrated ammoniumhydroxide) followed by recrystallization from acetonitrile to affordN-(9-methyl-9-azabicyclo[3.3.1]non-3-yl)-6-bromo-2-p-tolylbenzoxazole-4-carboxamide(30 mg, 25%) as a white solid: ¹H NMR (300 MHz, CDCl₃) δ 8.94 (d, J=7.3Hz, 1H), 8.33 (d, J=1.8 Hz, 1H), 8.12 (d, J=8.2 Hz, 2H), 7.83 (d, J=1.9Hz, 1H), 7.39 (d, J=8.0 Hz, 2H), 4.63-4.50 (m, 1H), 3.12 (d, J=10.6 Hz,2H), 2.70-2.55 (m, 2H), 2.54 (s, 3H), 2.48 (s, 3H), 2.20-1.95 (m, 2H),1.65-1.45 (m, 4H), 1.20-1.10 (m, 2H); MS (ESI+) m/z 468 (M+H); HPLC98.4% (AUC), t_(R)=14.06 min.

Example 86 Preparation ofN-(1-Azabicyclo[2.2.2]oct-3-yl)-6-bromo-2-(4-methoxyphenyl)benzoxazole-4-carboxamide

Step A: To a suspension of 2-amino-5-bromo-3-hydroxybenzoic acid (311mg, 1.00 mmol) in dichloromethane (10 mL) was added pyridine (0.48 mL,6.00 mmol) followed by p-anisoyl chloride (512 mg, 3.00 mmol) at roomtemperature. The resulting reaction mixture was stirred at roomtemperature for 20 min, then DMAP (24 mg, 0.20 mmol) was added and thereaction mixture was stirred at room temperature overnight. The reactionwas quenched with aqueous 2 N HCl (50 mL). The reaction mixture wasextracted with ethyl acetate, and the organic layer was washed withbrine, dried over Na₂SO₄, filtered and concentrated to give a yellowsolid. The crude was dissolved in toluene (10 mL) and the solution wastreated with p-toluenesulfonic acid monohydrate (328 mg, 1.72 mmol). Thereaction mixture was then heated to reflux under nitrogen overnight. Thereaction was cooled down to room temperature, poured into water andextracted with ethyl acetate. The combined organic layers were washedwith water, brine, dried over Na₂SO₄, filtered and concentrated to givea yellow solid. The crude product was purified by column chromatography(silica gel, 9:1 to 3:1 ethyl acetate/methanol) to afford the desiredproduct (172 mg, 49%) as an off-white solid: MS (ESI+) m/z 348 (M+H).

Step B: A mixture of 6-bromo-2-(4-methoxyphenyl)benzoxazole-4-carboxylicacid from Step A (86 mg, 0.25 mmol),1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (94 mg, 0.49mmol), 1-hydroxybenzotriazole (67 mg, 0.49 mmol) and(±)-3-aminoquinuclidine dihydrochloride (59 mg, 0.30 mmol) in DMF (5 mL)was stirred 10 min at room temperature, then triethylamine (0.10 mL,0.99 mmol) was added. The resulting reaction mixture was stirred at roomtemperature for 12 h. The mixture was diluted with ethyl acetate andthen washed with a saturated solution of sodium bicarbonate. The aqueouslayer was further extracted with ethyl acetate (2×100 mL). The combinedorganic layers were dried (Na₂SO₄), filtered and concentrated. The crudematerial was purified by column chromatography (silica gel, 90:9:1 ethylacetate/methanol/concentrated ammonium hydroxide) to affordN-(1-azabicyclo[2.2.2]oct-3-yl)-6-bromo-2-(4-methoxyphenyl)benzoxazole-4-carboxamide(56 mg, 50%) as a white solid: ¹H NMR (500 MHz, CDCl₃) δ 9.47 (d, J=7.0Hz, 1H), 8.29 (d, J=1.7 Hz, 1H), 8.20-8.10 (m, 2H), 7.83 (d, J=1.7 Hz,1H), 7.06 (d, J=8.8 Hz, 2H), 4.45-4.35 (m, 1H), 3.93 (s, 3H), 3.55-3.45(m, 1H), 3.15-3.00 (m, 2H), 2.95-2.90 (m, 2H), 2.85-2.75 (m, 1H),2.20-2.15 (m, 1H), 2.10-2.00 (m, 1H), 1.80-1.75 (m, 2H), 1.70-1.55 (m,1H); MS (ESI+) m/z 456 (M+H); HPLC 96.9% (AUC), t_(R)=14.64 min.

Example 87 Preparation ofN-(9-Methyl-9-azabicyclo[3.3.1]non-3-yl)-6-bromo-2-(4-methoxyphenyl)benzoxazole-4-carboxamide

A mixture of 6-bromo-2-(4-methoxyphenyl)benzoxazole carboxylic acid (86mg, 0.25 mmol), 1-ethyl-3-(3-dimethylaminopropyl)carbodiimidehydrochloride (94 mg, 0.49 mmol), 1-hydroxybenzotriazole (67 mg, 0.49mmol) and 3-amino-9-methyl-9-azabicyclo[3.3.1]nonane dihydrochloride (67mg, 0.30 mmol) in DMF (5 mL) was stirred for 10 min at room temperature,then triethylamine (0.100 mL, 0.99 mmol) was added. The resultingreaction mixture was stirred at room temperature for 18 h. The mixturewas diluted with ethyl acetate and then washed with a saturated solutionof sodium bicarbonate. The aqueous layer was further extracted withethyl acetate (2×100 mL). The combined organic layers were washed withbrine (2×100 mL), dried (Na₂SO₄), filtered and concentrated. The crudematerial was purified by column chromatography (silica gel, 90:9:1 ethylacetate/methanol/concentrated ammonium hydroxide) to affordN-(9-methyl-9-azabicyclo[3.3.1]non-3-yl)-6-bromo-2-(4-methoxyphenyl)benzoxazole-4-carboxamide(32 mg, 27%) as a white solid: ¹H NMR (500 MHz, CDCl₃) δ 8.99 (br s,1H), 8.30 (d, J=1.8 Hz, 1H), 8.17 (d, J=8.8 Hz, 2H), 7.81 (d, J=1.8 Hz,1H), 7.10-7.05 (m, 2H), 4.60-4.55 (m, 1H), 3.93 (s, 3H), 3.25-3.15 (m,2H), 2.70-2.55 (m, 5H), 2.40-2.00 (m, 3H), 1.70-1.20 (m, 5H); MS (ESI+)m/z 484 (M+H); HPLC >99% (AUC), t_(R)=15.30 min.

Example 88 Preparation ofN-(9-Methyl-9-azabicyclo[3.3.1]non-3-yl)-6-amino-2-phenylbenzoxazole-4-carboxamideDihydrochloride

Step A: A dry flask was charged withN-(9-methyl-9-azabicyclo[3.3.1]non-3-yl)-6-bromo-2-phenylbenzoxazole-4-carboxamide(454 mg, 1.00 mmol), tert-butyl carbamate (176 mg, 1.50 mmol), Pd(OAc)₂(22 mg, 0.10 mmol), xantphos (87 mg, 0.15 mmol) and cesium carbonate(489 mg, 1.50 mmol) and 1,4-dioxane (10 mL). The mixture was degassedwith argon. The resulting reaction mixture was heated at 100° C. for 12h. The reaction mixture was cooled to room temperature, and then dilutedwith methylene chloride and water. The reaction mixture was extractedwith methylene chloride (2×50 mL). The combined organic layers werewashed with brine, dried (Na₂SO₄) and concentrated under reducedpressure. The crude material was purified by column chromatography(silica gel, 90:9:1 methylene chloride/methanol/concentrated ammoniumhydroxide) to afford the carbamate (228 mg, 70%) as an off-white solid:¹H NMR (500 MHz, CDCl₃) δ 9.09 (br s, 1H), 8.40 (s, 1H), 8.25-8.15 (m,2H), 7.68 (d, J=1.9 Hz, 1H), 7.65-7.54 (m, 3H), 7.26 (s, 1H), 6.76 (s,1H), 4.60-4.55 (m, 1H), 3.40-3.20 (m, 2H), 2.90-2.65 (m, 6H), 2.15-2.00(m, 3H), 1.80-1.70 (m, 3H), 1.58 (s, 9H); MS (ESI+) m/z 491 (M+H).

Step B: To a solution of the carbamate from Step A (220 mg, 0.47 mmol)in methylene chloride (4 mL) was added TFA (2 mL) at 0° C. The reactionmixture was allowed to warm to room temperature and stirred for 2 h. Thereaction mixture was concentrated under reduced pressure. The residuewas dissolved in methanol and methylene chloride, and the solution wasdiluted with diethyl ether. The resulting precipitate was isolated byfiltration, dissolved in methylene chloride and treated with aqueous 10%Na₂CO₃. The aqueous layer was extracted with methylene chloride (3×50mL). The combined organic layers were washed with brine, dried (Na₂SO₄)and concentrated under reduced pressure to afford a yellow solid. Thecrude material was purified by preparative TLC (90:9:1 methylenechloride/methanol/concentrated ammonium hydroxide) to afford the desiredproduct (121 mg, 73%) as a light yellow solid: ¹H NMR (500 MHz, CDCl₃) δ9.09 (br s, 1H), 8.40 (s, 1H), 8.25-8.15 (m, 2H), 7.68 (d, J=1.9 Hz,1H), 7.65-7.54 (m, 3H), 7.26 (s, 1H), 6.76 (s, 1H), 4.60-4.55 (m, 1H),3.40-3.20 (m, 2H), 2.90-2.65 (m, 6H), 2.15-2.00 (m, 3H), 1.80-1.70 (m,4H); MS (ESI+) m/z 391 (M+1).

Step C: To a solution of the amide from Step B (120 mg, 0.31 mmol) inmethanol (1.0 mL) was added a solution of HCl in diethyl ether (1 N,0.93 mL, 0.93 mmol) at room temperature slowly. The reaction mixture wasdiluted with diethyl ether. The resulting solid was filtered and washedwith diethyl ether to affordN-(9-methyl-9-azabicyclo[3.3.1]non-6-amino-2-phenylbenzoxazole-4-carboxamidedihydrochloride (54 mg, 38%) as a yellow solid: ¹H NMR (500 MHz,DMSO-d₆) δ 10.48 (br s, 0.4H), 9.69 (br s, 0.6H), 9.16 (d, J=5.8 Hz,0.6H), 8.88 (d, J=6.9 Hz, 0.4H), 8.23-8.15 (m, 2H), 7.70-7.60 (m, 3H),7.55-7.50 (m, 1H), 7.36 (s, 1H), 4.90-4.35 (m, 4H), 3.70-3.65 (m, 1.4H),3.60-3.55 (m, 0.6H), 2.90-2.80 (m, 4H), 2.75-2.60 (m, 2H), 2.40-2.10 (m,3H), 1.95-1.82 (m, 2H), 1.60-1.50 (m, 2H); MS (ESI+) m/z 391 (M+H);HPLC >99% (AUC), t_(R)=11.49 min.

Example 89 Preparation ofN-(1-Azabicyclo[2.2.2]oct-3-yl)-5-bromo-2-phenylbenzoxazole-4-carboxamide

Step A: To a mixture of 3-methoxy-2-nitrobenzoic acid (2.5 g, 12.7 mmol)and silver sulfate (2.0 g, 6.4 mmol) in concd sulfuric acid (50 mL) wasadded bromine (2.03 g, 12.7 mmol), then the reaction mixture was stirredat room temperature in the dark for 2 h. Water was then added, and theresulting precipitate was collected. The solid was dissolved in acetoneand the residue was filtered off. The filtrate was dried (MgSO₄),filtered and concentrated to afford the brominated product (2.64 g, 75%)as an off-white solid: ¹H NMR (500 MHz, DMSO-d₆) δ 14.50 (br s, 1H),7.92 (d, J=9.0 Hz, 1H), 7.42 (d, J=9.0 Hz, 1H), 3.93 (s, 3H).

Step B: A mixture of the brominated product from Step A (1.3 g, 4.71mmol) in hydrobromic acid (48% in H₂O, 7 mL) and glacial acetic acid(0.6 mL) was refluxed for 12 h. After cooled to room temperature, thereaction mixture was neutralized by the addition of 6 N NaOH and theaqueous layer was extracted with dichloromethane. The combined organicswere dried (Na₂SO₄), filtered and concentrated. The crude material waspurified by column chromatography (silica gel, 9:1 to 3:1 ethylacetate/methanol) to afford the desired product (1.6 g, quantitative) asa brown solid: ¹H NMR (300 MHz, DMSO-d₆) δ 11.5 (br s, 1H), 7.40 (d,J=8.7 Hz, 1H), 6.85 (d, J=8.7 Hz, 1H), 3.72 (s, 1H); MS (ESI−) m/z 260(M−H).

Step C: To a solution of 2-nitro-6-bromo-3-hydroxybenzoic acid from StepB (1.23 g, 4.71 mmol) in THF (110 mL) was added a solution of sodiumhydrosulfite (4.80 g, 23.6 mmol) in water (60 mL), then the resultingreaction mixture was warmed to 60° C. for 0.5 h. After cooled to roomtemperature, the organic layer was separated and the aqueous layer wasextracted with ethyl acetate (2×80 mL). The combined organics werewashed with brine, dried (Na₂SO₄), filtered and concentrated. The crudematerial was purified by column chromatography (silica gel, 9:1 to 3:1ethyl acetate/methanol) to afford amino acid (0.51 g, 47%) as a brownsolid: ¹H NMR (500 MHz, DMSO-d₆) δ 6.56 (d, J=8.5 Hz, 1H), 6.53 (d,J=8.5 Hz, 1H), 3.75 (s, 1H), 2.01 (s, 3H); MS (ESI+) m/z 232 (M+H).

Step D: To a suspension of 2-amino-6-bromo-3-hydroxybenzoic acid (500mg, 2.15 mmol) in dichloromethane (15 mL) was added pyridine (1.1 mL,12.9 mmol) followed by benzoyl chloride (0.75 mL, 6.45 mmol) at roomtemperature. The resulting reaction mixture was stirred at roomtemperature for 10 min, then DMAP (52 mg, 0.43 mmol) was added and thereaction mixture was stirred at room temperature overnight. The reactionwas quenched with aqueous 2 N HCl and the solution was stirred for 30min. The aqueous layer was extracted with dichloromethane. The organiclayers were washed with brine and dried over Na₂SO₄, filtered andconcentrated to give a brown solid. The crude product was dissolved intoluene (15 mL) and the solution was treated with p-toluenesulfonic acidmonohydrate (409 mg, 2.15 mmol). The reaction mixture was then heated toreflux overnight. The reaction was cooled down to room temperature,poured into water and extracted with ethyl acetate. The organic layerwas separated then washed with water, brine, dried over Na₂SO₄, filteredand concentrated. The crude product was purified by columnchromatography (silica gel, 9:1 to 3:1 ethyl acetate/methanol) to affordthe desired product (0.30 g, 44%) as a brown solid: ¹H NMR (500 MHz,DMSO-d₆) δ 12.5 (br s, 1H), 8.17 (dd, J=7.5, 2.0 Hz, 2H), 7.68-7.61 (m,3H), 7.52-7.45 (m, 2H); MS (ESI+) m/z 318 (M+H).

Step E: A mixture of phenylbenzoxazole carboxylic acid from Step D (180mg, 0.56 mmol), (±)-3-aminoquinuclidine dihydrochloride (134 mg, 0.67mmol), 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (215mg, 1.12 mmol) and 1-hydroxybenzotriazole (151 mg, 1.12 mmol) in DMF(2.5 mL) was stirred for 5 min at room temperature, then triethylamine(0.31 mL, 2.24 mmol) was added. The resulting reaction mixture wasstirred at room temperature for 12 h. The mixture was diluted withdichloromethane (20 mL), then washed with a saturated solution of sodiumbicarbonate (10 mL). The aqueous layer was further extracted withdichloromethane (3×15 mL). The combined organics were dried (Na₂SO₄),filtered and concentrated. The crude material was purified by columnchromatography (silica gel, 89:10:1dichloromethane/methanol/concentrated ammonium hydroxide) followed byrecrystallization from ethyl acetate to affordN-(1-azabicyclo[2.2.2]oct-3-yl)-5-bromo-2-phenylbenzoxazole-4-carboxamide(20 mg, 8%) as an off-white solid: ¹H NMR (500 MHz, CDCl₃) δ 8.25 (d,J=5.5 Hz, 1H), 8.24-8.21 (m, 2H), 7.68 (d, J=8.5 Hz, 1H), 7.62-7.54 (m,3H), 7.52 (d, J=8.5 Hz, 1H), 4.38-4.28 (m, 1H), 3.53 (ddd, J=11.5, 9.5,2.0 Hz, 1H), 3.10-2.85 (m, 4H), 2.80 (dd, J=14.0, 4.5 Hz, 1H), 2.21 (dt,J=6.0, 3.0 Hz, 1H), 2.10-2.02 (m, 1H), 1.79-1.74 (m, 2H), 1.64-1.61 (m,1H); MS (ESI+) m/z 426 (M+H); HPLC 98.4% (AUC), t_(R)=11.29 min.

Example 90 Preparation ofN-(9-Methyl-9-azabicyclo[3.3.1]non-3-yl)-5-bromo-2-phenylbenzoxazole-4-carboxamide

A mixture of 5-bromo-2-phenylbenzo[d]oxazole-4-carboxylic acid (180 mg,0.56 mmol), 3-amino-9-methyl-9-azabicyclo[3.3.1]nonane dihydrochloride(152 mg, 0.67 mmol), 1-ethyl-3-(3-dimethylaminopropyl)carbodiimidehydrochloride (215 mg, 1.12 mmol) and 1-hydroxybenzotriazole (151 mg,1.12 mmol) in DMF (2.5 mL) was stirred for 5 min at room temperature,then triethylamine (0.31 mL, 2.24 mmol) was added. The resultingreaction mixture was stirred at room temperature for 12 h. The mixturewas diluted with dichloromethane (20 mL), then washed with a saturatedsolution of sodium bicarbonate (10 mL). The aqueous layer was furtherextracted with dichloromethane (3×15 mL). The combined organics weredried (Na₂SO₄), filtered and concentrated. The crude material waspurified by column chromatography (silica gel, 89:10:1dichloromethane/methanol/concentrated ammonium hydroxide) to affordN-(9-methyl-9-azabicyclo[3.3.1]non-3-yl)-5-bromo-2-phenylbenzoxazole-4-carboxamide(31 mg, 12%) as a white solid: ¹H NMR (500 MHz, CDCl₃) δ 8.25-8.23 (m,2H), 7.62 (d, J=8.5 Hz, 1H), 7.60-7.53 (m, 3H), 7.48 (d, J=8.5 Hz, 1H),7.12 (br s, 1H), 4.69-4.63 (m, 1H), 3.13 (d, J=10.0 Hz, 2H), 2.67 (td,J=12.5, 7.0 Hz, 2H), 2.54 (s, 3H), 2.05-1.93 (m, 3H), 1.60-1.52 (m, 1H),1.43 (t, J=11.0 Hz, 2H), 1.15-1.10 (m, 2H); MS (ESI+) m/z 454 (M+H);HPLC 98.4% (AUC), t_(R)=11.89 min.

Example 91 Preparation ofN-(9-Methyl-9-azabicyclo[3.3.1]non-3-yl)-7-bromo-2-phenylbenzoxazole-4-carboxamide

Step A: To a suspension of 3-hydroxy-2-nitrobenzoic acid (2.0 g, 10.9mmol) in acetic acid (4 mL) was added a solution of bromine (0.59 mL,11.4 mmol) in acetic acid (3 mL) dropwise via a addition funnel over 0.5h, then the reaction mixture was stirred in the dark at 60° C. for 12 h.After cooled to room temperature, the reaction mixture was concentratedto give the desired product as a yellow solid (contained 30% ofdi-brominated products). The crude product was dissolved in THF (90 mL)and a solution of sodium hydrosulfite (11.2 g, 54.5 mmol) in water (50mL) was added. The reaction mixture was stirred at 60° C. for 40 min.After the reaction mixture was cooled to room temperature, the aqueouslayer was separated and extracted with ethyl acetate. The combinedorganics were dried (Na₂SO₄), filtered and concentrated. The crudematerial was purified by column chromatography (silica gel, 4:1 ethylacetate/hexane to 3:1 ethyl acetate/methanol) to afford the desiredproduct (1.17 g, 46%) as a pale-brown solid (contained 20% isomer): ¹HNMR (500 MHz, DMSO-d₆) δ 9.20 (br s, 1H), 7.21 (d, J=8.5 Hz, 1H), 6.65(d, J=8.5 Hz, 1H), 3.32 (s, 3H).

Step B: To a suspension of 2-amino-4-bromo-3-hydroxybenzoic acid (1.16g, 5.00 mmol) in dichloromethane (40 mL) was added pyridine (2.4 mL, 30mmol) followed by benzoyl chloride (1.7 mL, 15 mmol) at roomtemperature. The resulting reaction mixture was stirred at roomtemperature for 10 min, then DMAP (122 mg, 1.0 mmol) was added and thereaction mixture was stirred at room temperature overnight. The reactionwas quenched with aqueous 2 N HCl and the solution was stirred for 30min. The aqueous layer was extracted with dichloromethane. The organiclayers were washed with brine and dried over Na₂SO₄, filtered andconcentrated to give a brown solid. The crude product was dissolved intoluene (35 mL) and the solution was treated with p-toluenesulfonic acidmonohydrate (950 mg, 5.0 mmol). The reaction mixture was then heated toreflux overnight. The reaction was cooled down to room temperature,poured into water and extracted with ethyl acetate. The organic layerwas separated then washed with water, brine, dried over Na₂SO₄, filteredand concentrated. The crude product was purified by columnchromatography (silica gel, 9:1 to 3:1 ethyl acetate/methanol) to affordthe desired product (0.75 g, 47%) as a pale-brown solid: ¹H NMR (500MHz, DMSO-d₆) δ 13.50 (br s, 1H), 8.25-8.20 (m, 2H), 7.86-7.80 (m, 2H),7.68-7.58 (m, 3H); MS (ESI+) m/z 318 (M+H).

Step C: A mixture of phenylbenzoxazole carboxylic acid from Step B (200mg, 0.62 mmol), 3-amino-9-methyl-9-azabicyclo[3.3.1]nonanedihydrochloride (100 mg, 0.62 mmol),1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (237 mg,1.24 mmol) and 1-hydroxybenzotriazole (167 mg, 1.24 mmol) in DMF (2.5mL) was stirred for 5 min at room temperature, then triethylamine (0.34mL, 2.48 mmol) was added. The resulting reaction mixture was stirred atroom temperature for 12 h. The mixture was diluted with dichloromethane(20 mL), then washed with a saturated solution of sodium bicarbonate (10mL). The aqueous layer was further extracted with dichloromethane (3×15mL). The combined organics were dried (Na₂SO₄), filtered andconcentrated. The crude material was purified by column chromatography(silica gel, 89:10:1 dichloromethane/methanol/concentrated ammoniumhydroxide) followed by semi-preparative HPLC to affordN-(9-methyl-9-azabicyclo[3.3.1]non-3-yl)-7-bromo-2-phenylbenzoxazole-4-carboxamide(44 mg, 16%) as a white solid: ¹H NMR (500 MHz, CDCl₃) δ 8.86 (d, J=7.5Hz, 1H), 8.30-8.28 (m, 2H), 8.10 (d, J=8.5 Hz, 1H), 7.68-7.57 (m, 4H),4.61-4.55 (m, 1H), 3.12 (d, J=10.5 Hz, 2H), 2.67-2.60 (m, 2H), 2.54 (s,3H), 2.23-1.98 (m, 3H), 1.63-1.58 (m, 1H), 1.49 (t, J=10.5 Hz, 2H),1.21-1.14 (m, 2H); MS (ESI+) m/z 454 (M+H); HPLC >99% (AUC), t_(R)=13.56min.

Example 92 Preparation ofN-(1-Azabicyclo[2.2.2]oct-3-yl)-7-bromo-2-phenylbenzoxazole-4-carboxamide

A mixture of 7-bromo-2-phenylbenzo[d]oxazole-4-carboxylic acid (200 mg,0.62 mmol), (±)-3-aminoquinuclidine dihydrochloride (148 mg, 0.74 mmol),1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (237 mg,1.24 mmol) and 1-hydroxybenzotriazole (167 mg, 1.24 mmol) in DMF (2.5mL) was stirred 5 min at room temperature, then triethylamine (0.34 mL,2.48 mmol) was added. The resulting reaction mixture was stirred at roomtemperature for 12 h. The mixture was diluted with dichloromethane (20mL), then washed with a saturated solution of sodium bicarbonate (10mL). The aqueous layer was further extracted with dichloromethane (3×15mL). The combined organics were dried (Na₂SO₄), filtered andconcentrated. The crude material was purified by column chromatography(silica gel, 89:10:1 dichloromethane/methanol/concentrated ammoniumhydroxide) followed by semi-preparative HPLC to affordN-(1-azabicyclo[2.2.2]oct-3-yl)-7-bromo-2-phenylbenzoxazole-4-carboxamide(34 mg, 13%) as a white solid: ¹H NMR (500 MHz, CDCl₃) δ 9.41 (d, J=7.0Hz, 1H), 8.29-8.26 (m, 2H), 8.09 (d, J=8.5 Hz, 1H), 7.66-7.57 (m, 4H),4.31-4.27 (m, 1H), 3.51 (ddd, J=11.5, 9.5, 2.0 Hz, 1H), 3.15-2.85 (m,4H), 2.81 (dd, J=14.0, 4.0 Hz, 1H), 2.17-2.14 (m, 1H), 2.07-2.02 (m,1H), 1.79-1.61 (m, 3H); MS (ESI+) m/z 426 (M+H); HPLC >99% (AUC),t_(R)=13.09 min.

Example 93 Preparation ofN-(1-Azabicyclo[2.2.2]oct-3-yl)-6-iodo-2-phenylbenzoxazole-4-carboxamide

Step A: To a solution of methyl 2-amino-3-methoxybenzoate (2.00 g, 11.0mmol) in ethanol (25 mL) was added silver sulfate (3.61 g, 11.6 mmol).To the above mixture was added iodine (2.94 g, 11.6 mmol). The resultingmixture was stirred at room temperature for 3 h. The reaction mixturewas diluted with methylene chloride and water. The aqueous layer wasseparated and extracted with methylene chloride (2×100 mL). The combinedorganic layers were washed with a saturated solution of sodium hydrogensulfite (2×100 mL), brine, dried over Na₂SO₄, filtered and concentratedto afford a dark brown solid. The crude material was purified by columnchromatography (silica gel, 95:5 hexanes/ethyl acetate) to afford thedesired product (2.49 g, 74%) as an off-white solid: ¹H NMR (300 MHz,CDCl₃) δ 7.60 (d, J=2.1 Hz, 1H), 6.90 (d, J=2.1 Hz, 1H), 6.03 (br s,2H), 3.86 (s, 6H); MS (ESI+) m/z 308 (M+H).

Step B: To a mixture of methyl 2-amino-5-iodo-3-methoxybenzoate fromStep A (307 mg, 1.00 mmol) in methylene chloride (2.5 mL) was added asolution of boron tribromide (2.2 mL, 1.0 M in CH₂Cl₂, 2.2 mmol) slowlyat −78° C. and stirred at −78° C. for 30 min, then at 0° C. for 1 h andat room temperature for 10 h. The reaction was quenched with methanoland concentrated to afford the desired product (0.31 g, quantitative) asa brown solid: ¹H NMR (300 MHz, DMSO-d₆) δ 10.10 (br s, 1H), 7.48 (d,J=2.0 Hz, 1H), 7.03 (d, J=2.0 Hz, 1H), 4.80 (br s, 3H); MS (ESI+) m/z280 (M+H).

Step C: To a suspension of 2-amino-5-iodo-3-hydroxybenzoic acid (300 mg,1.0 mmol) in dichloromethane (10 mL) was added pyridine (0.25 mL, 3.0mmol) followed by benzoyl chloride (428 mg, 3.1 mmol) at roomtemperature. The resulting reaction mixture was stirred at roomtemperature for 20 min then DMAP (25 mg, 0.20 mmol) was added, and thereaction mixture was stirred at room temperature overnight. The reactionwas quenched with aqueous 2 N HCl (50 mL). The reaction mixture wasextracted with dichloromethane. The combined organic layers were driedover Na₂SO₄, filtered and concentrated to give a yellow solid. The crudewas dissolved in toluene (10 mL) and the solution was treated withp-toluenesulfonic acid monohydrate (298 mg, 1.57 mmol). The reactionmixture was then heated to reflux under nitrogen for 24 h. The reactionwas cooled down to room temperature, poured into water and extractedwith ethyl acetate. The organic layer was separated then washed withwater, brine, dried over Na₂SO₄, filtered and concentrated to give ayellow solid. The crude product was purified by column chromatography(silica gel, 9:1 to 3:1 ethyl acetate/methanol) to afford the desiredproduct (158 mg, 42%) as an off-white solid: ¹H NMR (500 MHz, DMSO-d₆) δ8.49 (d, J=1.6 Hz, 1H), 8.25-8.20 (m, 2H), 8.16 (d, J=1.6 Hz, 1H),7.70-7.60 (m, 3H); MS (ESI+) m/z 366 (M+H).

Step D: A mixture of 6-iodo-2-phenylbenzoxazole-4-carboxylic acid fromStep C (75 mg, 0.21 mmol), 1-ethyl-3-(3-dimethylaminopropyl)carbodiimidehydrochloride (78 mg, 0.41 mmol), 1-hydroxybenzotriazole (55 mg, 0.41mmol) and (±)-3-aminoquinuclidine dihydrochloride (50 mg, 0.25 mmol) inDMF (5 mL) was stirred for 10 min at room temperature, thentriethylamine (0.08 mL, 0.82 mmol) was added. The resulting reactionmixture was stirred at room temperature for 12 h. The mixture wasdiluted with ethyl acetate (50 mL), and then washed with a saturatedsolution of sodium bicarbonate. The aqueous layer was further extractedwith ethyl acetate (3×50 mL). The combined organics were dried (Na₂SO₄),filtered and concentrated. The crude material was purified by columnchromatography (silica gel, 90:9:1 methylenechloride/methanol/concentrated ammonium hydroxide) to affordN-(1-azabicyclo[2.2.2]oct-3-yl)-6-iodo-2-phenylbenzoxazole-4-carboxamide(52 mg, 53%) as an off-white solid: ¹H NMR (500 MHz, CDCl₃) δ 9.44 (d,J=7.1 Hz, 1H), 8.49 (d, J=1.5 Hz, 1H), 8.25-8.15 (m, 2H), 8.08 (d, J=1.6Hz, 1H), 7.65-7.52 (m, 3H), 4.35-4.30 (m, 1H), 3.60-3.50 (m, 1H),3.16-3.05 (m, 2H), 3.00-2.90 (m, 2H), 2.85 (dd, J=14.2, 3.5 Hz, 1H),2.22-2.17 (m, 1H), 2.12-2.05 (m, 1H), 1.85-1.78 (m, 2H), 1.75-1.63 (m,1H); MS (ESI+) m/z 474 (M+H); HPLC >99% (AUC), t_(R)=13.41 mm.

Example 94 Preparation ofN-(9-Methyl-9-azabicyclo[3.3.1]non-3-yl)-6-iodo-2-phenylbenzoxazole-4-carboxamide

A mixture of 6-iodo-2-phenylbenzoxazole-4-carboxylic acid (75 mg, 0.21mmol), 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (78mg, 0.41 mmol), 1-hydroxybenzotriazole (55 mg, 0.41 mmol) and3-amino-9-methyl-9-azabicyclo[3.3.1]nonane dihydrochloride (69 mg, 0.25mmol) in DMF (5 mL) was stirred 10 min at room temperature, thentriethylamine (0.10 mL, 0.82 mmol) was added. The resulting reactionmixture was stirred at room temperature overnight. The mixture wasdiluted with diethyl ether (50 mL) and then washed with a saturatedsolution of sodium bicarbonate. The aqueous layer was further extractedwith ethyl acetate (2×50 mL). The combined organics were dried (Na₂SO₄),filtered and concentrated under reduced pressure. The crude material waspurified by column chromatography (silica gel, 90:9:1 methylenechloride/methanol/concentrated ammonium hydroxide) followed byrecrystallization from acetonitrile to affordN-(9-methyl-9-azabicyclo[3.3.1]non-3-yl)-6-iodo-2-phenylbenzoxazole-4-carboxamide(64 mg, 63%) as a light yellow solid: ¹H NMR (500 MHz, CDCl₃) δ 8.91 (brs, 1H), 8.52 (d, J=1.6 Hz, 1H), 8.25-8.20 (m, 2H), 8.06 (d, J=1.5 Hz,1H), 7.65-7.55 (m, 3H), 4.65-4.52 (m, 1H), 3.32-3.10 (m, 2H), 2.70-2.50(m, 5H), 2.20-1.20 (m, 2H), 1.65-1.45 (m, 4H), 1.25-1.10 (m, 2H); MS(ESI+) m/z 502 (M+H); HPLC >99% (AUC), t_(R)=13.83 min.

Example 95 Preparation ofN-(1-Azabicyclo[2.2.2]oct-3-yl)-6-morpholine-2-phenylbenzoxazole-4-carboxamide

A reaction tube was charged withN-(1-azabicyclo[2.2.2]oct-3-yl)-6-bromo-2-phenylbenzoxazole-4-carboxamide(50 mg, 0.12 mmol), morpholine (0.10 mL, 1.15 mmol), Pd(OAc)₂ (7.0 mg,0.03 mmol), xantphos (25 mg, 0.04 mmol) and cesium carbonate (54 mg,0.16 mmol) in DMF (0.1 mL). The reaction tube was exposed to microwaveirradiation for 14 min at 130° C. The reaction tube was thereaftercooled to room temperature and reaction mixture was extracted withmethylene chloride. The combined organic layers were washed with water,brine, dried over sodium sulfate and concentrated to give a yellowsolid. The crude was purified by semi-preparative HPLC to affordN-(1-azabicyclo[2.2.2]oct-3-yl)-6-morpholine-2-phenylbenzoxazole-4-carboxamide(7 mg, 34%) as a light yellow solid: ¹H NMR (500 MHz, CDCl₃) δ 9.55 (d,J=7.3 Hz, 1H), 8.20-8.15 (m, 2H), 7.82 (d, J=2.4 Hz, 1H), 7.57-7.52 (m,3H), 7.19 (d, J=2.4 Hz, 1H), 4.35-4.27 (m, 1H), 3.91 (t, J=4.7 Hz, 4H),3.57-3.50 (m, 1H), 3.29 (t, J=4.8 Hz, 4H), 3.15-3.00 (m, 2H), 2.95-2.90(m, 2H), 2.85 (dd, J=14.1, 3.9 Hz, 1H), 2.17-2.14 (m, 1H), 2.13-2.03 (m,1H), 1.80-1.73 (m, 2H), 1.70-1.60 (m, 1H); MS (ESI+) m/z 433 (M+H); HPLC97.5% (AUC), t_(R)=20.59 min.

Example 96 Preparation ofN-(1-Azabicyclo[2.2.2]oct-3-yl)-6-amino-2-phenylbenzoxazole-4-carboxamide

Step A: A dry flask was charged withN-(1-azabicyclo[2.2.2]oct-3-yl)-6-bromo-2-phenylbenzoxazole-4-carboxamide(300 mg, 0.70 mmol), tert-butyl carbamate (124 mg, 1.06 mmol), Pd(OAc)₂(16 mg, 0.07 mmol), xantphos (61 mg, 0.11 mmol) and cesium carbonate(321 mg, 0.99 mmol) in 1,4-dioxane (3 mL). The mixture was degassed withargon. The resulting reaction mixture was heated at 100° C. for 12 h.The reaction mixture was cooled to room temperature, diluted withmethylene chloride and water. The reaction mixture was extracted withmethylene chloride (2×50 mL). The combined organic layers were washedwith brine, dried (Na₂SO₄) and concentrated under reduced pressure. Thecrude material was purified by column chromatography (silica gel, 90:9:1methylene chloride/methanol/concentrated ammonium hydroxide) to affordthe compound (228 mg, 70%) as an off-white solid: ¹H NMR (500 MHz,CDCl₃) δ 9.51 (d, J=7.3 Hz, 1H), 8.41 (s, 1H), 8.19 (dd, J=8.2, 1.3 Hz,2H), 7.67 (d, J=1.9 Hz, 1H), 7.70-7.54 (m, 3H), 6.80 (s, 1H), 4.45-4.30(m, 1H), 3.55-3.47 (m, 1H), 3.15-2.98 (m, 2H), 2.95-2.87 (m, 2H), 2.82(dd, J=14.1, 3.9 Hz, 1H), 2.17-2.14 (m, 1H), 2.12-2.03 (m, 1H),1.80-1.73 (m, 2H), 1.65-1.60 (m, 1H), 1.58 (s, 9H); MS (ESI+) m/z 463(M+H).

Step B: To a solution of carbamate obtained in Step A (220 mg, 0.47mmol) in methylene chloride (4 mL) was added TFA (2 mL) at 0° C. Thereaction mixture was allowed to warm to room temperature and stirred for2 h. The reaction mixture was concentrated under reduced pressure. Thesolid was dissolved in methanol and methylene chloride, and then diethylether was added. The resulting precipitate was isolated by filtration,dissolved in methylene chloride and treated with 10% Na₂CO₃. The aqueouslayer was extracted with methylene chloride (3×50 mL). The combinedorganic layers were washed with brine, dried (Na₂SO₄) and concentratedunder reduced pressure to afford a yellow solid. The solid was furtherpurified by recrystallization from ethyl acetate to affordN-(1-azabicyclo[2.2.2]oct-3-yl)-6-amino-2-phenylbenzoxazole-4-carboxamide(115 mg, 67%) as a yellow solid: ¹H NMR (500 MHz, CDCl₃) δ 9.55 (d,J=7.4 Hz, 1H), 8.19-8.15 (m, 2H), 7.55-7.50 (m, 4H), 6.97 (d, J=2.0 Hz,1H), 4.30-4.24 (m, 1H), 3.99 (br s, 2H), 3.52-3.45 (m, 1H), 3.13-2.98(m, 2H), 2.95-2.87 (m, 2H), 2.82 (dd, J=14.3, 4.0 Hz, 1H), 2.15-2.12 (m,1H), 2.10-2.05 (m, 1H), 1.77-1.72 (m, 2H), 1.65-1.60 (m, 1H); MS (ESI+)m/z 363 (M+H); HPLC 98.3% (AUC), t_(R)=20.00 min.

Example 97 Preparation ofN-(1-Azabicyclo[2.2.2]oct-3-yl)-6-acetylamino-2-phenylbenzoxazole-4-carboxamide

To a solution ofN-(1-azabicyclo[2.2.2]oct-3-yl)-6-amino-2-phenylbenzoxazole-4-carboxamide(35 mg, 0.09 mmol) in methylene chloride (1 mL) was added pyridine (11μL, 0.14 mmol) and acetic anhydride (11 μL, 0.10 mmol) at 0° C. andstirred for 30 min, then allowed to warm to room temperature for 1 h.The reaction mixture was quenched with saturated solution of sodiumbicarbonate and concentrated under reduced pressure. The crude waspurified by semi-preparative HPLC to affordN-(1-azabicyclo[2.2.2]oct-3-yl)-6-acetylamino-2-phenylbenzoxazole-4-carboxamide(13 mg, 44%) as a light yellow solid: ¹H NMR (500 MHz, CDCl₃) δ 9.58 (d,J=7.4 Hz, 1H), 8.73 (d, J=1.9 Hz, 1H), 8.20 (d, J=6.8 Hz, 1H), 8.13 (s,1H), 7.81 (d, J=1.7 Hz, 1H), 7.55-7.50 (m, 4H), 4.35-4.27 (m, 1H),3.57-3.48 (m, 1H), 3.16-3.03 (m, 2H), 2.97-2.82 (m, 2H), 2.27 (s, 3H),2.17-2.05 (m, 2H), 1.85-1.60 (m, 3H); MS (ESI+) m/z 405 (M+H); HPLC >99%(AUC), t_(R)=23.81 min.

Example 98 Preparation of(S)-N-(1-Azabicyclo[2.2.2]oct-3-yl)-6-methoxy-2-phenylbenzoxazole-4-carboxamide

Step A: To a suspension of 6-bromo-2-phenylbenzoaxazole-4-carboxylicacid (480 mg, 1.51 mmol) in a mixture of toluene and methanol (10 mL)was added trimethylsilyldiazomethane (1.51 mL, 2.0 M in ether, 3.01mmol) at room temperature. The resulting reaction mixture was stirred atroom temperature for 10 min. The reaction was quenched with aqueousacetic acid (0.25 mL) and concentrated to remove solvents. The reactionmixture was extracted with dichloromethane. The organic layer was washedwith brine, dried over Na₂SO₄, filtered and concentrated to afford thedesired product (485 mg, 96%) as an off-white solid: ¹H NMR (500 MHz,CDCl₃) δ 8.34-8.30 (m, 2H), 8.15 (d, J=1.9 Hz, 1H), 7.93 (d, J=1.8 Hz,1H), 7.10-6.95 (m, 3H), 4.06 (s, 3H); MS (ESI+) m/z 333 (M+H).

Step B: A mixture of 6-bromo-2-phenylbenzoaxazole-4-carboxylic acidmethyl ester from Step A (485 mg, 1.46 mmol), bis(pinacolato)diboron(463 mg, 1.83 mmol), potassium acetate (429 mg, 4.38 mmol) in DMF (5 mL)was degassed and refilled with argon, then PdCl₂(dppf) (119 mL, 0.15mmol) was added. The resulting reaction mixture was degassed, refilledwith argon and then heated at 80° C. for 10 h. The mixture was dilutedwith ethyl acetate and then washed with water. The aqueous layer wasfurther extracted with ethyl acetate (2×100 mL). The combined organiclayers were dried (Na₂SO₄), filtered and concentrated to afford thedesired product (553 mg, quantitative) as a brown solid: ¹H NMR (500MHz, CDCl₃) δ 8.46 (d, J=0.9 Hz, 1H), 8.38-8.34 (m, 2H), 7.93 (d, J=0.9Hz, 1H), 7.56-7.50 (m, 3H), 4.06 (s, 3H), 1.38 (s, 12H); MS (ESI+) m/z380 (M+H).

Step C: To a vigorously stirred solution of sodium hydroxide (80 mg,2.19 mmol) in 8 mL of water was added boronate obtained from Step B (553mg, 1.46 mmol) at 0° C. followed by sodium bicarbonate (491 mg, 5.84mmol) and acetone (2.5 mL) and then the mixture was stirred for 5 min.To the above solution was added oxone (1.35 g, 2.19 mmol) and then themixture was stirred at 0° C. for 20 min. The reaction was quenched with10% NaHSO₄ solution and pH was adjusted to 7 by addition of 1 N HCl. Thereaction was extracted with ethyl acetate (2×100 mL), and the combinedorganic layers were washed with brine, dried over Na₂SO₄ andconcentrated under reduced pressure to afford the desired product (590mg, quantitative) as a brown solid: ¹H NMR (300 MHz, CDCl₃) δ 8.30-8.20(m, 2H), 7.60-7.45 (m, 5H), 7.33-7.25 (m, 1H), 4.05 (s, 3H); MS (ESI+)m/z 270 (M+H).

Step D: To a stirred solution of compound obtained in Step C (400 mg,1.4 mmol) in DMF (6 mL) was added cesium carbonate (2.4 g, 7.4 mmol) andmethyl iodide (1.05 g, 7.4 mmol) at room temperature. The resultingreaction mixture was stirred at room temperature for 10 h. The reactionmixture was extracted with ethyl acetate (3×100 mL). The combinedorganic layers were washed with water (4×50 mL), brine (2×50 mL), driedover Na₂SO₄, filtered and concentrated. The crude material was purifiedby column chromatography (silica gel, 8:2 hexanes/ethyl acetate) toafford the desired product (156 mg, 37%) as a brown solid: ¹H NMR (500MHz, CDCl₃) δ 8.32-8.28 (m, 2H), 8.62 (d, J=2.5 Hz, 1H), 7.55-7.50 (m,3H), 7.32 (d, J=2.5 Hz, 1H), 4.07 (s, 3H), 3.93 (s, 3H); MS (ESI+) m/z284 (M+H).

Step E: A mixture of the compound obtained in step D (156 mg, 0.55 mmol)and lithium hydroxide monohydrate (35 mg, 0.83 mmol) in a mixture oftetrahydrofuran/methanol/water (2:1:1, 4 mL) was heated at 100° C. for 2h. The reaction mixture was concentrated to dryness and treated with 2 NHCl to adjust the pH to 4. The reaction mixture was extracted with ethylacetate (2×50 mL), and the combined organic layers were washed withbrine, dried over Na₂SO₄, filtered and concentrated to afford thedesired product (131 mg, 89%) as a light brown solid: ¹H NMR (500 MHz,DMSO-d₆) δ 13.17 (br s, 1H), 8.20-8.17 (m, 2H), 7.70 (d, J=2.5 Hz, 1H),7.64-7.60 (m, 3H), 7.45 (d, J=2.5 Hz, 1H), 7.10-6.95 (m, 3H), 3.90 (s,3H); MS (ESI+) m/z 270 (M+H).

Step F: A mixture of 6-methoxy-2-phenylbenzoxazole-4-carboxylic acid (50mg, 0.18 mmol), 1-ethyl-3-(3-dimethylaminopropyl)carbodiimidehydrochloride (71 mg, 0.37 mmol), 1-hydroxybenzotriazole (50 mg, 0.37mmol) and (S)-(−)-3-aminoquinuclidine dihydrochloride (46 mg, 0.23 mmol)in DMF (3 mL) was stirred at room temperature for 10 min, thentriethylamine (0.10 mL, 0.72 mmol) was added. The resulting reactionmixture was stirred at room temperature overnight. The mixture wasdiluted with dichloromethane and then washed with a saturated solutionof sodium bicarbonate. The aqueous layer was further extracted withdichloromethane (2×50 mL). The combined organic layers were washed withbrine (2×50 mL), dried (Na₂SO₄), filtered and concentrated. The crudematerial was purified by column chromatography (silica gel, 90:9:1 ethylacetate/methanol/concentrated ammonium hydroxide) to afford(S)-N-(1-azabicyclo[2.2.2]oct-3-yl)-6-methoxy-2-phenylbenzoxazole-4-carboxamide(55 mg, 76%) as a white solid: ¹H NMR (500 MHz, CDCl₃) δ 9.56 (d, J=7.2Hz, 1H), 8.21-8.17 (m, 2H), 7.79 (d, J=2.5 Hz, 1H), 7.60-7.52 (m, 3H),7.26-7.24 (m, 1H), 4.34-4.30 (m, 1H), 3.94 (s, 3H), 3.56-3.51 (m, 1H),3.16-3.05 (m, 2H), 2.95-2.84 (m, 3H), 2.20-2.18 (m, 1H), 2.15-2.03 (m,1H), 1.82-1.76 (m, 2H), 1.70-1.55 (m, 1H); MS (ESI+) m/z 378 (M+H);HPLC >99% (AUC), t_(R)=12.90 min.

Example 99 Preparation ofN-(9-Methyl-9-azabicyclo[3.3.1]non-3-yl)-6-methoxy-2-phenylbenzoxazole-4-carboxamide

A mixture of 6-methoxy-2-phenylbenzoxazole-4-carboxylic acid (100 mg,0.35 mmol), 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride(134 mg, 0.70 mmol), 1-hydroxybenzotriazole (95 mg, 0.70 mmol) and3-amino-9-methyl-9-azabicyclo[3.3.1]nonane dihydrochloride (99 mg, 0.44mmol) in DMF (3 mL) was stirred at room temperature for 10 min, thentriethylamine (0.20 mL, 1.40 mmol) was added. The resulting reactionmixture was stirred at room temperature overnight. The mixture wasdiluted with dichloromethane and then washed with a saturated solutionof sodium bicarbonate. The aqueous layer was further extracted withdichloromethane (2×50 mL). The combined organic layers were washed withwater (2×50 mL), brine (2×50 mL), dried (Na₂SO₄), filtered andconcentrated. The crude material was purified by column chromatography(silica gel, 90:9:1 dichloromethane/methanol/concentrated ammoniumhydroxide) and recrystallization from acetonitrile to affordN-(9-methyl-9-azabicyclo[3.3.1]non-3-yl)-6-methoxy-2-phenylbenzoxazole-4-carboxamide(24 mg, 16%) as a light yellow solid: ¹H NMR (500 MHz, CDCl₃) δ 9.08 (brs, 1H), 8.21-8.19 (m, 2H), 7.81 (d, J=2.5 Hz, 1H), 7.59-7.54 (m, 3H),7.23 (d, J=2.5 Hz, 1H), 4.65-4.55 (m, 1H), 3.93 (s, 3H), 3.25-3.10 (m,2H), 2.70-2.55 (m, 5H), 2.27-2.00 (m, 3H), 1.65-1.55 (m, 3H), 1.35-1.20(m, 2H); MS (ESI+) m/z 406 (M+H); HPLC >99% (AUC), t_(R)=13.14 min.

Example 100 Preparation of(S)-N-(1-Azabicyclo[2.2.2]oct-3-yl)-6-hydroxy-2-phenylbenzoxazole-4-carboxamide

Step A: A mixture of 6-hydroxy-2-phenylbenzo[d]oxazole-4-carboxylic acid(190 mg, 0.71 mmol) and lithium hydroxide monohydrate (45 mg, 1.07 mmol)in a mixture of tetrahydrofuran/methanol/water (2:1:1, 4 mL) was heatedat 100° C. for 1 h. The reaction mixture was concentrated to dryness andtreated with 2 N HCl to adjust the pH to 4. The reaction mixture wasextracted with ethyl acetate (25 mL) and the combined organic layerswere washed with water (25 mL), brine (25 mL), dried over Na₂SO₄,filtered and concentrated to afford the desired product (107 mg, 57%) asa light brown solid: ¹H NMR (500 MHz, DMSO-d₆) δ 13.05 (br s, 1H), 10.18(s, 1H), 8.20-8.16 (m, 2H), 7.65-7.50 (m, 3H), 7.40-7.32 (m, 2H); MS(ESI+) m/z 256 (M+H).

Step B: A mixture of 6-hydroxy-2-phenylbenzoxazole-4-carboxylic acid(104 mg, 0.35 mmol), 1-ethyl-3-(3-dimethylaminopropyl)carbodiimidehydrochloride (134 mg, 0.70 mmol), 1-hydroxybenzotriazole (95 mg, 0.70mmol) and (S)-(−)-3-aminoquinuclidine dihydrochloride (87 mg, 0.44 mmol)in DMF (3 mL) was stirred at room temperature for 10 min, thentriethylamine (0.20 mL, 1.4 mmol) was added. The resulting reactionmixture was stirred at room temperature overnight. The mixture wasdiluted with dichloromethane and then washed with a saturated solutionof sodium bicarbonate. The aqueous layer was further extracted withdichloromethane (2×50 mL). The combined organic layers were washed withbrine (2×50 mL), dried (Na₂SO₄), filtered and concentrated. The crudematerial was purified by column chromatography (silica gel, 90:9:1 ethylacetate/methanol/concentrated ammonium hydroxide) and recrystallizationfrom acetonitrile to afford(S)-N-(1-azabicyclo[2.2.2]oct-3-yl)-6-hydroxy-2-phenylbenzoxazole-4-carboxamide(29 mg, 30%) as a white solid: ¹H NMR (500 MHz, CDCl₃) δ 10.22 (br s,1H), 9.29 (d, J=7.4 Hz, 1H), 8.17-8.13 (m, 2H), 7.67-7.63 (m, 3H), 7.46(d, J=2.3 Hz, 1H), 7.32 (d, J=2.3 Hz, 1H), 4.09-4.06 (m, 1H), 3.30-3.27(m, 1H), 2.90-2.86 (m, 2H), 2.77-2.72 (m, 2H), 2.62-2.59 (m, 1H),1.99-1.94 (m, 2H), 1.69-1.63 (m, 3H); MS (ESI+) m/z 364 (M+H); HPLC >99%(AUC), t_(R)=11.90 min.

Example 101 Preparation of(S)-N-(1-Azabicyclo[2.2.2]oct-3-yl)-6-fluoro-2-phenylbenzoxazole-4-carboxamide

Step A: Iodine (3.6 g, 14.2 mmol) was added to a mixture of methyl2-amino-5-fluorobenzoate (2.4 g, 14.2 mmol), silver sulfate (4.42 g,14.2 mmol) and ethanol (30 mL) at room temperature. The mixture wasstirred under nitrogen for 1 h, and then quenched with a saturatedsolution of sodium bicarbonate, extracted with ethyl acetate. Thecombined organic layers were washed with brine, dried (Na₂SO₄), filteredand concentrated. The crude material was purified by columnchromatography (silica gel, 90:10 hexanes/ethyl acetate) to affordiodide (3.9 g, 93%) as a light yellow solid: ¹H NMR (300 MHz, CDCl₃) δ7.66-7.58 (m, 2H), 6.21 (br s, 2H), 3.89 (s, 3H); ¹⁹F NMR (282 MHz,CDCl₃) δ −127.87; MS (ESI+) m/z 296 (M+H).

Step B: A mixture of the iodide from Step A (500 mg, 1.69 mmol),bis(pinacolato)diboron (515 mg, 2.03 mmol), potassium acetate (497 mg,5.07 mmol), and toluene (10 mL) was degassed with nitrogen for 15 min.PdCl₂(dppf) (277 mg, 0.34 mmol) was added. The mixture was heated at100° C. under nitrogen for 24 h and then cooled to room temperature,quenched with a saturated solution of sodium bicarbonate, extracted withethyl acetate. The combined organic layers were washed with brine, dried(Na₂SO₄), filtered and concentrated. The crude material was purified bycolumn chromatography (silica gel, 90:10 hexanes/ethyl acetate) toafford borate (264 mg, 53%) as a light yellow solid: ¹H NMR (300 MHz,CDCl₃) δ 7.64 (dd, J=9.6, 3.3 Hz, 1H), 7.52 (dd, J=8.1, 3.3 Hz, 1H),6.88 (br s, 2H), 3.85 (s, 3H), 1.35 (s, 12H); ¹⁹F NMR (282 MHz, CDCl₃) δ−131.16; MS (ESI+) m/z 296 (M+H).

Step C: Benzoyl chloride (88 μL, 0.76 mmol) was added to a solution ofthe amine from Step B (180 mg, 0.61 mmol) in methylene chloride (2 mL)at room temperature, followed by triethylamine (0.17 mL, 1.22 mmol). Themixture was stirred under nitrogen overnight and then quenched with asaturated solution of sodium bicarbonate, extracted with methylenechloride. The combined organic layers were washed with brine, dried(Na₂SO₄), filtered and concentrated. The crude material was purified bycolumn chromatography (silica gel, 50:50 hexanes/ethyl acetate) toafford amide (150 mg, 62%) as a white solid: ¹H NMR (500 MHz, CDCl₃) δ13.10 (br s, 1H), 8.08-8.06 (m, 2H), 7.71-7.58 (m, 5H), 4.01 (s, 3H),1.40 (s, 12H); MS (ESI+) m/z 400 (M+H).

Step D: To a solution of sodium hydroxide (22 mg, 0.56 mmol) and sodiumbicarbonate (126 mg, 1.50 mmol) in water (5 mL), was added oxone (364mg, 0.564 mmol) at 0° C., followed by the borate from Step C (150 mg,0.376 mmol) in acetone (3 mL). The mixture was allowed to warm to roomtemperature and stirred for 30 min, and then quenched with water,extracted with methylene chloride. The combined organic layers werewashed with brine, dried (Na₂SO₄), filtered and concentrated to give thephenol (92 mg, 85%) as a light yellow solid: ¹H NMR (300 MHz, CDCl₃) δ11.95 (br s, 1H), 10.61 (s, 1H), 8.10-8.07 (m, 2H), 7.65-7.55 (m, 3H),7.37 (dd, J=8.4, 3.0 Hz, 1H), 7.03 (dd, J=8.4, 3.0 Hz, 1H), 3.98 (s,3H); ¹⁹F NMR (282 MHz, CDCl₃) δ −115.50; MS (ESI+) m/z 290 (M+H).

Step E: A mixture of the amide from Step D (90 mg, 0.31 mmol),p-toluenesulfonic acid monohydrate (89 mg, 0.47 mmol) and toluene (4 mL)was heated at reflex under nitrogen for 1 h. The reaction mixture wasthen cooled to room temperature, diluted with ethyl acetate, washed witha saturated solution of sodium bicarbonate and brine, dried over sodiumsulfate, filtered and concentrated to afford the benzoxazole (69 mg,84%) as a light yellow solid: ¹H NMR (300 MHz, CDCl₃) δ 8.34-8.30 (m,2H), 7.78 (dd, J=8.4, 3.0 Hz, 1H), 7.56-7.50 (m, 4H), 4.07 (s, 3H); ¹⁹FNMR (282 MHz, CDCl₃) δ −114.95; MS (ESI+) m/z 272 (M+H).

Step F: A mixture of the ester from Step E (68 mg, 0.25 mmol), 2 N NaOH(1.0 mL, 2.0 mmol), methanol (2 mL) and THF (2 mL) was stirred at roomtemperature under nitrogen overnight. The reaction mixture was acidifiedwith 1 N HCl, extracted with methylene chloride, washed with brine,dried over sodium sulfate, filtered and concentrated to afford the acid(60 mg, 93%) as a light yellow solid: ¹H NMR (300 MHz, CDCl₃) δ 11.50(br s, 1H), 8.30-8.26 (m, 2H), 7.90 (dd, J=9.6, 2.4 Hz, 1H), 7.64-7.55(m, 4H); ¹⁹F NMR (282 MHz, CDCl₃) δ −111.75; MS (ESI+) m/z 258 (M+H).

Step G: A mixture of the carboxylic acid from Step F (30 mg, 0.12 mmol),(S)-3-aminoquinuclidine dihydrochloride (28 mg, 0.14 mmol),1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (46 mg, 0.24mmol) and 1-hydroxybenzotriazole (32 mg, 0.24 mmol) in DMF (5 mL) wasstirred under nitrogen at room temperature for 10 min, and thentriethylamine (0.10 mL, 0.72 mmol) was added. The resulting reactionmixture was stirred at room temperature overnight, and then was quenchedwith a saturated solution of sodium bicarbonate, extracted withmethylene chloride. The combined organic layers were dried (Na₂SO₄),filtered and concentrated. The crude material was purified by columnchromatography (silica gel, 90:9:1 ethyl acetate/methanol/concentratedammonium hydroxide) to afford(S)-N-(1-azabicyclo[2.2.2]oct-3-yl)-6-fluoro-2-phenylbenzoxazole-4-carboxamide(38 mg, 88%) as a light yellow solid: ¹H NMR (500 MHz, CDCl₃) δ 9.50 (d,J=7.0 Hz, 1H), 8.21-8.19 (m, 2H), 7.93 (dd, J=10.5, 2.5 Hz, 1H),7.63-7.55 (m, 3H), 7.45 (dd, J=7.0, 2.5 Hz, 1H), 4.32-4.28 (m, 1H), 3.52(ddd, J=14.0, 9.5, 2.0 Hz, 1H), 3.10-2.81 (m, 5H), 2.17-2.06 (m, 2H),1.80-1.62 (m, 3H); ¹⁹F NMR (282 MHz, CDCl₃) δ −113.64; MS (ESI+) m/z 366(M+H); HPLC >99% (AUC), t_(R)=12.17 min.

Example 102 Preparation ofN-(9-Methyl-9-azabicyclo[3.3.1]non-3-yl)-6-fluoro-2-phenyl)benzoxazole-4-carboxamide

A mixture of 6-fluoro-2-phenylbenzo[d]oxazole-4-carboxylic acid (30 mg,0.12 mmol), 3-amino-9-methyl-9-azabicyclo[3.3.1]nonane dihydrochloride(32 mg, 0.14 mmol), 1-ethyl-3-(3-dimethylaminopropyl)carbodiimidehydrochloride (46 mg, 0.24 mmol) and 1-hydroxybenzotriazole (32 mg, 0.24mmol) in DMF (5 mL) was stirred under nitrogen at room temperature for10 min, and then triethylamine (0.10 mL, 0.72 mmol) was added. Theresulting reaction mixture was stirred at room temperature overnight,and then was quenched with a saturated solution of sodium bicarbonate,extracted with methylene chloride. The combined organic layers werewashed with brine, dried (Na₂SO₄), filtered and concentrated. The crudematerial was purified by column chromatography (silica gel, 90:9:1 ethylacetate/methanol/concentrated ammonium hydroxide) to affordN-(9-methyl-9-azabicyclo[3.3.1]non-3-yl)-6-fluoro-2-phenyl)benzoxazole-4-carboxamide(42 mg, 91%) as a light yellow solid: ¹H NMR (500 MHz, CDCl₃) δ 8.96 (d,J=7.5 Hz, 1H), 8.23-8.22 (m, 2H), 7.96 (d, J=10.5 Hz, 1H), 7.63-7.55 (m,3H), 7.42 (d, J=7.0 Hz, 1H), 4.62-4.53 (m, 1H), 3.13-3.11 (m, 2H),2.67-2.60 (m, 2H), 2.54 (s, 3H), 2.15-1.98 (m, 3H), 1.62-1.46 (m, 3H),1.18-1.13 (m, 2H); ¹⁹F NMR (282 MHz, CDCl₃) δ −113.93; MS (ESI+) m/z 394(M+H); HPLC >99% (AUC), t_(R)=12.78 min.

Example 103 Preparation of(S)-N-(1-Azabicyclo[2.2.2]oct-3-yl)-6-fluoro-2-(2-methoxyphenyl)benzoxazole-4-carboxamideHydrochloride

Step A: Iodine (3.6 g, 14.2 mmol) was added to a mixture of methyl2-amino-5-fluorobenzoate (2.4 g, 14.2 mmol), silver sulfate (4.42 g,14.2 mmol) and ethanol (30 mL) at room temperature. The mixture wasstirred under nitrogen for 1 h, and then quenched with a saturatedsolution of sodium bicarbonate, extracted with ethyl acetate. Thecombined organic layers were washed with brine, dried (Na₂SO₄), filteredand concentrated. The crude material was purified by columnchromatography (silica gel, 90:10 hexanes/ethyl acetate) to affordiodide (3.9 g, 93%) as a light yellow solid: ¹H NMR (300 MHz, CDCl₃) δ7.66-7.58 (m, 2H), 6.21 (br s, 2H), 3.89 (s, 3H); ¹⁹F NMR (282 MHz,CDCl₃) δ −127.87; MS (ESI+) m/z 296 (M+H).

Step B: A mixture of the iodide from Step A (500 mg, 1.69 mmol),bis(pinacolato)diboron (515 mg, 2.03 mmol), potassium acetate (497 mg,5.07 mmol), and toluene (10 mL) was degassed with nitrogen for 15 min.PdCl₂(dppf) (277 mg, 0.34 mmol) was added. The mixture was heated at100° C. under nitrogen for 24 h and then cooled to room temperature,quenched with a saturated solution of sodium bicarbonate, extracted withethyl acetate. The combined organic layers were washed with brine, dried(Na₂SO₄), filtered and concentrated. The crude material was purified bycolumn chromatography (silica gel, 90:10 hexanes/ethyl acetate) toafford borate (264 mg, 53%) as a light yellow solid: ¹H NMR (300 MHz,CDCl₃) δ 7.64 (dd, J=9.6, 3.3 Hz, 1H), 7.52 (dd, J=8.1, 3.3 Hz, 1H),6.88 (br s, 2H), 3.85 (s, 3H), 1.35 (s, 12H); ⁹F NMR (282 MHz, CDCl₃) δ−131.16; MS (ESI+) m/z 296 (M+H).

Step C: 2-Anisoyl chloride (0.16 mL, 1.06 mmol) was added to a solutionof the amine from Step B (260 mg, 0.88 mmol) in methylene chloride (4mL) at room temperature, followed by triethylamine (0.24 mL, 1.76 mmol).The mixture was stirred under nitrogen overnight and then quenched witha saturated solution of sodium bicarbonate, extracted with methylenechloride. The combined organic layers were washed with brine, dried(Na₂SO₄), filtered and concentrated. The crude material was purified bycolumn chromatography (silica gel, 50:50 hexanes/ethyl acetate) toafford amide (350 mg, 93%) as a white solid: ¹H NMR (300 MHz, CDCl₃) δ13.74 (br s, 1H), 8.34 (dd, J=8.1, 2.1 Hz, 1H), 7.67 (d, J=8.7 Hz, 2H),7.19-6.85 (m, 3H), 4.18 (s, 3H), 3.96 (s, 3H), 1.39 (s, 12H); ¹⁹F NMR(282 MHz, CDCl₃) δ −115.91; MS (ESI+) m/z 430 (M+H).

Step D: To a solution of sodium hydroxide (49 mg, 1.2 mmol) and sodiumbicarbonate (274 mg, 3.26 mmol) in water (10 mL) at 0° C., was addedoxone (750 mg, 1.22 mmol), followed by the borate from Step C (350 mg,0.816 mmol) in acetone (20 mL). The mixture was allowed to warm to roomtemperature and stirred for 4 h, and then quenched with water, extractedwith methylene chloride. The combined organic layers were washed withbrine, dried (Na₂SO₄), filtered and concentrated. The crude material waspurified by Combi-flash chromatography (silica gel, 80:20 hexanes/ethylacetate) to afford amide (213 mg, 82%) as a white solid: ¹H NMR (300MHz, CDCl₃) δ 12.18 (br s, 1H), 9.63 (s, 1H), 8.27 (dd, J=8.1, 1.8 Hz,1H), 7.60-7.52 (m, 1H), 7.30 (dd, J=8.4, 3.0 Hz, 1H), 7.14-7.00 (m, 3H),4.11 (s, 3H), 3.91 (s, 3H); ¹⁹F NMR (282 MHz, CDCl₃) δ −115.40; MS(ESI+) m/z 320 (M+H).

Step E: A mixture of the amide from Step D (213 mg, 0.668 mmol),p-toluenesulfonic acid monohydrate (127 mg, 0.668 mmol) and toluene (10mL) was heated at reflex under nitrogen for 2 h. The reaction mixturewas then cooled to room temperature, diluted with ethyl acetate, washedwith a saturated solution of sodium bicarbonate and brine, dried oversodium sulfate, filtered and concentrated. The crude material waspurified by Combi-flash chromatography (silica gel, 70:30 hexanes/ethylacetate) to afford benzoxazole (85 mg, 42%) as a white solid: ¹H NMR(300 MHz, CDCl₃) δ 8.21 (dd, J=8.1, 1.8 Hz, 1H), 7.77 (dd, J=8.4, 3.0Hz, 1H), 7.56-7.50 (m, 2H), 7.13-7.07 (m, 2H), 4.06 (s, 3H), 4.02 (s,3H); ¹⁹F NMR (282 MHz, CDCl₃) δ −114.92; MS (ESI+) m/z 302 (M+H).

Step F: A mixture of the ester from Step E (85 mg, 0.28 mmol), 2 N NaOH(1.0 mL, 2.0 mmol), methanol (2 mL) and THF (2 mL) was stirred at roomtemperature under nitrogen overnight. The reaction mixture was acidifiedwith 1 N HCl, extracted with methylene chloride, washed with brine,dried over sodium sulfate, filtered and concentrated to afford the acid(80 mg, 99%) as a white solid: ¹H NMR (300 MHz, CDCl₃) δ 11.90 (br s,1H), 8.17 (dd, J=8.1, 1.8 Hz, 1H), 7.87 (dd, J=8.4, 3.0 Hz, 1H),7.63-7.50 (m, 2H), 7.17-7.07 (m, 2H), 4.03 (s, 3H); ¹⁹F NMR (282 MHz,CDCl₃) δ −112.37; MS (ESI+) m/z 288 (M+H).

Step G: A mixture of the carboxylic acid from Step F (40 mg, 0.14 mmol),(S)-3-aminoquinuclidine dihydrochloride (34 mg, 0.17 mmol),1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (54 mg, 0.28mmol) and 1-hydroxybenzotriazole (38 mg, 0.28 mmol) in DMF (4 mL) wasstirred under nitrogen at room temperature for 10 min, and thentriethylamine (0.12 mL, 0.84 mmol) was added. The resulting reactionmixture was stirred at room temperature overnight, and then was quenchedwith a saturated solution of sodium bicarbonate, extracted withmethylene chloride. The combined organic layers were dried (Na₂SO₄),filtered and concentrated. The crude material was purified byCombi-flash chromatography (silica gel, 90:9:1 ethylacetate/methanol/concentrated ammonium hydroxide) to afford the desiredamide (33 mg, 60%) as a light yellow solid: ¹H NMR (300 MHz, CDCl₃) δ9.60 (d, J=7.0 Hz, 1H), 8.11 (dd, J=8.1, 1.8 Hz, 1H), 7.91 (dd, J=10.2,2.7 Hz, 1H), 7.60-7.54 (m, 1H), 7.44 (dd, J=7.2, 2.7 Hz, 1H), 7.16-7.11(m, 2H), 4.32-4.22 (m, 1H), 4.01 (s, 3H), 3.52 (ddd, J=14.0, 9.5, 2.0Hz, 1H), 3.10-2.78 (m, 5H), 2.19-1.96 (m, 2H), 1.80-1.52 (m, 3H); ¹⁹FNMR (282 MHz, CDCl₃) δ −113.94; MS (ESI+) m/z 396 (M+H).

Step H: Hydrogen chloride in diethyl ether (1.0 M, 0.17 mL, 0.17 mmol)was added dropwise to a solution of the amide from Step G (33 mg, 0.083mmol) in methanol (1 mL) at room temperature. The mixture was stirredfor 5 min, and then diethyl ether (20 mL) was added. The resulting solidwas filtered, washed with diethyl ether, and dried under vacuumovernight to afford(S)-N-(1-azabicyclo[2.2.2]oct-3-yl)-6-fluoro-2-(2-methoxyphenyl)benzoxazole-4-carboxamidehydrochloride (28 mg, 78%) as a white solid: ¹H NMR (300 MHz, DMSO-d₆) δ10.12 (br s, 1H), 9.41 (d, J=6.3 Hz, 1H), 8.11-8.08 (m, 2H), 7.73-7.66(m, 2H), 7.36 (d, J=8.4 Hz, 1H), 7.21 (t, J=7.2 Hz, 1H), 4.45-4.38 (m,1H), 3.96 (s, 3H), 3.77 (t, J=14.0 Hz, 1H), 3.45-3.20 (m, 5H), 2.46-2.18(m, 2H), 2.04-1.92 (m, 3H); ⁹F NMR (282 MHz, DMSO-d₆) δ −113.91; MS(ESI+) m/z 396 (M+H); HPLC >99% (AUC), t_(R)=12.54 min.

Example 104 Preparation ofN-(9-Methyl-9-azabicyclo[3.3.1]non-3-yl)-6-fluoro-2-(2-methoxyphenyl)benzoxazole-4-carboxamideHydrochloride

Step A: A mixture of6-fluoro-2-(2-methoxyphenyl)benzo[d]oxazole-4-carboxylic acid (40 mg,0.14 mmol), 3-amino-9-methyl-9-azabicyclo[3.3.1]nonane dihydrochloride(39 mg, 0.17 mmol), 1-ethyl-3-(3-dimethylaminopropyl)carbodiimidehydrochloride (54 mg, 0.28 mmol) and 1-hydroxybenzotriazole (38 mg, 0.28mmol) in DMF (4 mL) was stirred under nitrogen at room temperature for10 min, and then triethylamine (0.12 mL, 0.84 mmol) was added. Theresulting reaction mixture was stirred at room temperature overnight,and then was quenched with a saturated solution of sodium bicarbonate,extracted with methylene chloride. The combined organic layers werewashed with brine, dried (Na₂SO₄), filtered and concentrated. The crudematerial was purified by Combi-flash chromatography (silica gel, 90:9:1ethyl acetate/methanol/concentrated ammonium hydroxide) to afford amide(41 mg, 69%) as a light yellow solid: ¹H NMR (300 MHz, CDCl₃) δ 9.20 (d,J=7.2 Hz, 1H), 8.12 (dd, J=8.1, 1.8 Hz, 1H), 7.92 (dd, J=10.2, 2.7 Hz,1H), 7.60-7.54 (m, 1H), 7.42 (dd, J=7.2, 2.7 Hz, 1H), 7.16-7.11 (m, 2H),4.67-4.53 (m, 1H), 4.03 (s, 3H), 3.23-3.15 (m, 2H), 2.72-2.60 (m, 2H),2.58 (s, 3H), 2.15-1.98 (m, 3H), 1.62-1.53 (m, 3H), 1.21-1.15 (m, 2H);¹⁹F NMR (282 MHz, CDCl₃) δ −113.78; MS (ESI+) m/z 424 (M+H).

Step B: Hydrogen chloride in diethyl ether (1.0 M, 0.19 mL, 0.19 mmol)was added dropwise to a solution of the amide from Step A (41 mg, 0.097mmol) in methanol (3 mL) at room temperature. The mixture was stirredfor 5 min, and then diethyl ether (30 mL) was added. The resulting solidwas filtered, washed with diethyl ether, and dried under vacuumovernight to affordN-(9-methyl-9-azabicyclo[3.3.1]non-3-yl)-6-fluoro-2-(2-methoxyphenyl)benzoxazole-4-carboxamidehydrochloride (25 mg, 57%) as a white solid: ¹H NMR (300 MHz, DMSO-d₆) δ10.25 (br s, 0.3H), 9.51 (br s, 0.7H), 9.31 (d, J=7.2 Hz, 0.3H), 9.08(d, J=7.2 Hz, 0.7H), 8.13-8.06 (m, 2H), 7.74-7.66 (m, 2H), 7.35 (d,J=8.4 Hz, 1H), 7.21 (t, J=7.2 Hz, 1H), 4.73-4.45 (m, 1H), 3.98 (s,2.1H), 3.96 (s, 0.9H), 3.73-3.55 (m, 2H), 2.82-2.60 (m, 2H), 2.50 (s,3H), 2.15-2.05 (m, 3H), 1.90-1.80 (m, 3H), 1.60-1.50 (m, 2H); ¹⁹F NMR(282 MHz, DMSO-d₆) δ −114.00; MS (ESI+) m/z 424 (M+H); HPLC >99% (AUC),t_(R)=12.52 mm.

Example 105 Preparation ofN-(9-Methyl-9-azabicyclo[3.3.1]non-3-yl)-2-pyridin-4-ylbenzoxazole-4-carboxamide

Step A: To a suspension of 2-amino-3-hydroxybenzoic acid hydrobromide(152 mg, 0.65 mmol) in dichloromethane (15 mL) was added pyridine (0.42ml, 5.2 mmol) followed by isonicotinoyl chloride hydrochloride (347 mg,1.95 mmol). The resulting reaction mixture was stirred at roomtemperature for 15 min and DMAP (16 mg, 0.13 mmol) was added, then thereaction mixture was stirred at room temperature overnight. Water (10mL) was added and the reaction was stirred at room temperature for 10min. The aqueous layer was extracted with ethyl acetate. The organiclayers were washed with brine, dried over Na₂SO₄, filtered andconcentrated. The product was dissolved in toluene (5 mL) and thesolution was treated with p-toluenesulfonic acid monohydrate (127 mg,0.67 mmol). The reaction mixture was then heated to reflux overnight.The reaction was cooled down to room temperature, poured into water andextracted with ethyl acetate. The organic layer was separated thenwashed with water, brine, dried over Na₂SO₄, filtered and concentratedto an orange solid. The crude product was purified by columnchromatography (silica gel, 9:1 to 2:1 ethyl acetate/methanol) to affordthe desired product (56 mg, 46%): ¹H NMR (500 MHz, CD₃OD) δ 8.77-8.76(m, 2H), 8.29-8.27 (m, 2H), 7.87 (d, J=7.5 Hz, 1H), 7.77 (d, J=8.5 Hz,1H), 7.49 (t, J=8.0 Hz, 1H); MS (ESI+) m/z 241 (M+H).

Step B: A mixture of 2-pyridin-4-ylbenzoxazole-4-carboxylic acid fromStep A (28 mg, 0.11 mmol), 3-amino-9-methyl-9-azabicyclo[3.3.1]nonanedihydrochloride (30 mg, 0.13 mmol),1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (30 mg, 0.16mmol) and 1-hydroxybenzotriazole (42 mg, 0.31 mmol) in DMF (5 mL) wasstirred for 10 min at room temperature, then DIPEA (0.09 mL, 0.55 mmol)was added. The resulting reaction mixture was stirred at roomtemperature overnight. The mixture was diluted with ethyl acetate (20mL), and then washed with a saturated solution of sodium bicarbonate.The aqueous layer was further extracted with ethyl acetate (2×50 mL).The combined organics were dried (Na₂SO₄), filtered and concentrated.The crude material was purified by semi-preparative HPLC to affordN-(9-methyl-9-azabicyclo[3.3.1]non-3-yl)-2-pyridin-4-ylbenzoxazole-4-carboxamide(15 mg, 36%) as a white solid: ¹H NMR (500 MHz, CDCl₃) δ 8.91-8.89 (m,2H), 8.82 (d, J=7.0 Hz, 1H), 8.28 (dd, J=7.5, 1.0 Hz, 1H), 8.09-8.08 (m,2H), 7.76 (dd, J=8.0, 0.5 Hz, 1H), 7.55 (t, J=8.0 Hz, 2H), 4.65-4.56 (m,1H), 3.14 (d, J=10.5 Hz, 2H), 2.69-2.62 (m, 1H), 2.55 (s, 3H), 2.19-2.00(m, 3H), 1.66-1.58 (m, 1H), 1.52-1.47 (m, 2H), 1.17 (d, J=11.5 Hz, 2H);MS (ESI+) m/z 377 (M+H); HPLC >99% (AUC), t_(R)=14.65 min.

Example 106 Preparation of(S)-N-(1-Azabicyclo[2.2.2]oct-3-yl)-2-furan-2-ylbenzoxazole-4-carboxamide

Step A: To a suspension of 2-amino-3-hydroxybenzoic acid hydrobromide(304 mg, 1.30 mmol) in dichloromethane (20 mL) was added pyridine (0.84mL, 10.4 mmol) followed by 2-furoyl chloride (0.39 ml, 3.9 mmol). Theresulting reaction mixture was stirred at room temperature for 15 min,then DMAP (32 mg, 0.26 mmol) was added and the reaction mixture wasstirred at room temperature overnight. Water (10 mL) was added and thereaction was stirred for 10 min. The reaction was quenched with aqueous1 N HCl (20 mL) until the solution reached pH 1. The solution wasstirred for 30 min. The aqueous layer was extracted with ethyl acetate.The organic layers were washed with brine and dried over Na₂SO₄,filtered and concentrated to a pale yellow solid. The product wasdirectly re-dissolved in toluene (10 mL) and the solution was treatedwith p-toluenesulfonic acid monohydrate (462 mg, 2.43 mmol). Thereaction mixture was then heated to reflux overnight. The reaction wascooled down to room temperature, poured into water and extracted withethyl acetate. The organic layer was separated then washed with water,brine, dried over Na₂SO₄, filtered and concentrated to a yellow solid.The crude product was purified by column chromatography (silica gel, 9:1to 2:1 ethyl acetate/methanol) to afford the desired product (102 mg,28%) as a pale orange solid: ¹H NMR (500 MHz, CD₃OD) δ 7.95 (d, J=9.0Hz, 1H), 7.65 (d, J=10.0 Hz, 1H), 7.45-7.37 (m, 2H), 7.31-7.27 (m, 1H),6.42 (s, 1H); MS (ESI+) m/z 230 (M+H).

Step B: A mixture of 2-furan-2-ylbenzoxazole-4-carboxylic acid from StepA (51 mg, 0.22 mmol), (S)-3-aminoquinuclidine dihydrochloride (52 mg,0.26 mmol), 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride(59 mg, 0.31 mmol) and 1-hydroxybenzotriazole (84 mg, 0.62 mmol) in DMF(5 mL) was stirred for 10 min at room temperature, then triethylamine(0.14 mL, 1.1 mmol) was added. The resulting reaction mixture wasstirred at room temperature overnight. The mixture was diluted withethyl acetate (20 mL), and then washed with a saturated solution ofsodium bicarbonate. The aqueous layer was further extracted with ethylacetate (2×50 mL). The combined organics were dried (Na₂SO₄), filteredand concentrated. The crude material was purified by columnchromatography (silica gel, 90:9:1 ethyl acetate/methanol/concentratedammonium hydroxide) to afford(S)-N-(1-azabicyclo[2.2.2]oct-3-yl)-2-furan-2-ylbenzoxazole-4-carboxamide(42 mg, 56%) as a white solid: ¹H NMR (500 MHz, CDCl₃) δ 9.51 (d, J=7.5Hz, 1H), 8.19 (dd, J=8.0, 1.0 Hz, 1H), 7.73 (m, 1H), 7.70 (dd, J=8.0,1.0 Hz, 1H), 7.47 (t, J=8.0 Hz, 1H), 7.33 (dd, J=3.5, 0.5 Hz, 1H),6.68-6.65 (m, 1H), 4.34-4.28 (m, 1H), 3.53-3.47 (m, 1H), 3.14-2.98 (m,2H), 2.93-2.89 (m, 3H), 2.16-2.04 (m, 1H), 1.81-1.58 (m, 4H); MS (ESI+)m/z 338 (M+H); HPLC >99% (AUC), t_(R)=11.59 min.

Example 107 Preparation ofN-(9-Methyl-9-azabicyclo[3.3.1]non-3-yl)-2-furan-2-ylbenzoxazole-4-carboxamide

A mixture of 2-furan-2-ylbenzoxazole-4-carboxylic acid (51 mg, 0.22mmol), 3-amino-9-methyl-9-azabicyclo[3.3.1]nonane dihydrochloride (59mg, 0.26 mmol), 1-ethyl-3-(3-dimethylaminopropyl)carbodiimidehydrochloride (59 mg, 0.31 mmol) and 1-hydroxybenzotriazole (84 mg, 0.62mmol) in DMF (5 mL) was stirred for 10 min at room temperature, thentriethylamine (0.14 mL, 1.1 mmol) was added. The resulting reactionmixture was stirred at room temperature overnight. The mixture wasdiluted with ethyl acetate (20 mL), and then washed with a saturatedsolution of sodium bicarbonate. The aqueous layer was further extractedwith ethyl acetate (2×50 mL). The combined organics were dried (Na₂SO₄),filtered and concentrated. The crude material was purified by columnchromatography (silica gel, 90:9:1 ethyl acetate/methanol/concentratedammonium hydroxide) to affordN-(9-methyl-9-azabicyclo[3.3.1]non-3-yl)-2-furan-2-ylbenzoxazole-4-carboxamide(49 mg, 61%) as an off-white solid: ¹H NMR (500 MHz, CDCl₃) δ 8.94 (d,J=6.0 Hz, 1H), 8.22 (dd, J=7.5, 1.0 Hz, 1H), 7.74 (d, J=1.5 Hz, 1H),7.68 (dd, J=8.0, 1.0 Hz, 1H), 7.46 (t, J=4.0 Hz, 1H), 7.35 (d, J=4.0 Hz,1H), 6.79-6.66 (m, 1H), 4.58-4.53 (m, 1H), 3.12 (d, J=10.0 Hz, 2H),2.66-2.59 (m, 2H), 2.55 (s, 3H), 2.18-1.98 (m, 3H), 1.68-1.49 (m, 3H),1.22-1.17 (m, 2H); MS (ESI+) m/z 366 (M+H); HPLC >99% (AUC), t_(R)=12.12mm.

Example 108 Preparation of(S)-N-(1-Azabicyclo[2.2.2]oct-3-yl)-2-thiophen-2-ylbenzoxazole-4-carboxamide

Step A: To a suspension of 2-amino-3-hydroxybenzoic acid hydrobromide(152 mg, 0.65 mmol) in dichloromethane (15 mL) was added pyridine (0.42mL, 5.2 mmol) followed by 2-thiophenecarbonyl chloride (0.21 ml, 1.95mmol). The resulting reaction mixture was stirred at room temperaturefor 15 min, then DMAP (16 mg, 0.13 mmol) was added and the reactionmixture was stirred at room temperature overnight. Water (10 mL) wasadded and the reaction stirred for 10 min. The reaction was quenchedwith aqueous 1 N HCl (30 mL) until the solution reached pH 1. Thesolution was stirred for 30 min. The aqueous layer was extracted withethyl acetate. The organic layers were washed with brine and dried overNa₂SO₄, filtered and concentrated to a yellow solid. The product wasdirectly re-dissolved in toluene (10 mL) and the solution was treatedwith p-toluenesulfonic acid monohydrate (262 mg, 1.38 mmol). Thereaction mixture was then heated to reflux overnight. The reaction wascooled down to room temperature, poured into water and extracted withethyl acetate. The organic layer was separated then washed with water,brine, dried over Na₂SO₄, filtered and concentrated to a yellow solid.The crude product was purified by column chromatography (silica gel, 9:1to 2:1 ethyl acetate/methanol) to afford the desired product (147 mg,65%) as a pale orange solid: MS (ESI+) m/z 246 (M+H).

Step B: A mixture of 2-thiophen-2-ylbenzoxazole-4-carboxylic acid fromStep A (64 mg, 0.26 mmol), (S)-3-aminoquinuclidine dihydrochloride (62mg, 0.31 mmol), 1-ethyl-3-(3-dimethylaminopropyl)carbodiimidehydrochloride (70 mg, 0.37 mmol) and 1-hydroxybenzotriazole (99 mg, 0.73mmol) in DMF (5 mL) was stirred for 10 min at room temperature, thentriethylamine (0.17 mL, 1.30 mmol) was added. The resulting reactionmixture was stirred at room temperature overnight. The mixture wasdiluted with ethyl acetate (20 mL), and then washed with a saturatedsolution of sodium bicarbonate. The aqueous layer was further extractedwith ethyl acetate (2×50 mL). The combined organics were dried (Na₂SO₄),filtered and concentrated. The crude material was purified by columnchromatography (silica gel, 90:9:1 ethyl acetate/methanol/concentratedammonium hydroxide) to afford(S)-N-(1-azabicyclo[2.2.2]oct-3-yl)-2-thiophen-2-ylbenzoxazole-4-carboxamide(58 mg, 63%) as a white solid: ¹H NMR (500 MHz, CDCl₃) δ 9.53 (d, J=7.5Hz, 1H), 8.18 (d, J=8.0 Hz, 1H), 7.94 (d, J=4.0 Hz, 1H), 7.68 (d, J=8.0Hz, 1H), 7.64 (d, J=5.0 Hz, 1H), 7.45 (t, J=8.0 Hz, 1H), 7.24 (t, J=4.0Hz, 1H), 4.33-4.30 (m, 1H), 3.52-3.47 (m, 1H), 3.16-2.99 (m, 2H),2.95-2.77 (m, 3H), 2.15-2.09 (m, 2H), 1.79-1.60 (m, 3H); MS (ESI+) m/z354 (M+H); HPLC >99% (AUC), t_(R)=24.25 min.

Example 109 Preparation ofN-(9-Methyl-9-azabicyclo[3.3.1]non-3-yl)-2-thiophen-2-ylbenzoxazole-4-carboxamide

A mixture of 2-thiophen-2-ylbenzoxazole-4-carboxylic acid (64 mg, 0.26mmol), 3-amino-9-methyl-9-azabicyclo[3.3.1]nonane dihydrochloride (70mg, 0.37 mmol), 1-ethyl-3-(3-dimethylaminopropyl)carbodiimidehydrochloride (99 mg, 0.52 mmol) and 1-hydroxybenzotriazole (99 mg, 0.74mmol) in DMF (5 mL) was stirred for 10 min at room temperature, thentriethylamine (0.17 mL, 1.3 mmol) was added. The resulting reactionmixture was stirred at room temperature overnight. The mixture wasdiluted with ethyl acetate (20 mL), and then washed with a saturatedsolution of sodium bicarbonate. The aqueous layer was further extractedwith ethyl acetate (2×50 mL). The combined organics were dried (Na₂SO₄),filtered and concentrated. The crude material was purified by columnchromatography (silica gel, 90:9:1 ethyl acetate/methanol/concentratedammonium hydroxide) and then recrystallized from acetonitrile to affordN-(9-methyl-9-azabicyclo[3.3.1]non-3-yl)-2-thiophen-2-ylbenzoxazole-4-carboxamide(55 mg, 56%) as an off-white solid: ¹H NMR (500 MHz, CDCl₃) δ 8.99 (d,J=7.0 Hz, 1H), 8.20 (dd, J=7.5, 0.5 Hz, 1H), 7.95 (dd, J=4.0, 1.0 Hz,1H), 7.67-7.63 (m, 2H), 7.45 (t, J=4.0 Hz, 1H), 7.27-7.23 (m, 1H),4.62-4.56 (m, 1H), 3.15-3.09 (m, 2H), 2.67-2.59 (m, 2H) 2.54 (s, 3H),2.18-1.88 (m, 3H), 1.65-1.57 (m, 5H); MS (ESI+) m/z 382 (M+H); HPLC >99%(AUC), t_(R)=24.24 min.

Example 110 Preparation ofN-(9-Methyl-9-azabicyclo[3.3.1]non-3-yl)-6-chloro-2-thiophen-2-ylbenzoxazole-4-carboxamide

Step A: To a mixture of 2-amino-3-hydroxy-5-chlorobenzoic acid (0.27 g,1.44 mmol) and 2-thiophenecarbonyl chloride (0.15 mL, 1.44 mmol) indichloromethane (10 mL) was added triethylamine (0.81 mL, 5.76 mmol)dropwise, then the reaction mixture was stirred at room temperature for12 h. The reaction mixture was diluted with dichloromethane, and thenwashed with 2 N HCl. The aqueous layer was extracted withdichloromethane. The combined organic layers were washed with brine,dried (Na₂SO₄), filtered and concentrated. The crude product wasdissolved in toluene (10 mL) and the solution was treated withp-toluenesulfonic acid monohydrate (249 mg, 1.31 mmol). The reactionmixture was then heated to reflux overnight. The reaction was cooleddown to room temperature, poured into water and extracted with ethylacetate. The organic layer was separated then washed with water, brine,dried (Na₂SO₄), filtered and concentrated. The crude product waspurified by column chromatography (silica gel, 9:1 to 3:1 ethylacetate/methanol) to afford the desired product (0.16 g, 44%) as a brownsolid: ¹H NMR (500 MHz, DMSO-d₆) δ 8.02 (d, J=3.0 Hz, 1H), 7.98 (dd,J=5.0, 1.0 Hz, 1H), 7.92 (d, J=2.0 Hz, 1H), 7.72 (s, 1H), 7.31 (dd,J=4.5, 4.0 Hz, 1H); MS (ESI+) m/z 279 (M+H).

Step B: A mixture of benzoxazole carboxylic acid from Step A (70 mg,0.25 mmol), 3-amino-9-methyl-9-azabicyclo[3.3.1]nonane dihydrochloride(57 mg, 0.25 mmol), 1-ethyl-3-(3-dimethylaminopropyl)carbodiimidehydrochloride (96 mg, 0.57 mmol) and 1-hydroxybenzotriazole (68 mg, 0.50mmol) in DMF (2 mL) was stirred at room temperature for 5 min, thentriethylamine (0.13 mL, 1.0 mmol) was added. The resulting reactionmixture was stirred at room temperature for 12 h. The mixture wasdiluted with dichloromethane (20 mL), then washed with a saturatedsolution of sodium bicarbonate (10 mL). The aqueous layer was furtherextracted with dichloromethane (3×15 mL). The combined organics weredried (Na₂SO₄), filtered and concentrated. The crude material waspurified by column chromatography (silica gel, 89:10:1dichloromethane/methanol/concentrated ammonium hydroxide) followed byrecrystallization from ethyl acetate to affordN-(9-methyl-9-azabicyclo[3.3.1]non-3-yl)-6-chloro-2-thiophen-2-ylbenzoxazole-4-carboxamide(40 mg, 38%) as an off-white solid: ¹H NMR (500 MHz, CDCl₃) δ 8.84 (d,J=6.5 Hz, 1H), 8.18 (d, J=2.0 Hz, 1H), 7.95 (dd, J=3.5, 1.0 Hz, 1H),7.67-7.64 (m, 2H), 7.26-7.23 (m, 1H), 4.58-4.52 (m, 1H), 3.12 (d, J=10.5Hz, 2H), 2.65-2.58 (m, 2H), 2.53 (s, 3H), 2.15-1.95 (m, 3H), 1.60-1.52(m, 1H), 1.48 (t, J=11.0 Hz, 2H), 1.18 (d, J=12.0 Hz, 2H); MS (ESI+) m/z416 (M+H); HPLC >99% (AUC), t_(R)=13.84 min.

Example 111 Preparation of(S)-N-(1-Azabicyclo[2.2.2]oct-3-yl)-6-chloro-2-thiophen-2-ylbenzoxazole-4-carboxamide

A mixture of 6-chloro-2-(thiophen-2-yl)benzo[d]oxazole-4-carboxylic acid(70 mg, 0.25 mmol), (S)-(−)-3-aminoquinuclidine dihydrochloride (50 mg,0.25 mmol), 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride(96 mg, 0.50 mmol) and 1-hydroxybenzotriazole (68 mg, 0.50 mmol) in DMF(2 mL) was stirred at room temperature for 5 min, then triethylamine(0.13 mL, 1.00 mmol) was added. The resulting reaction mixture wasstirred at room temperature for 12 h. The mixture was diluted withdichloromethane (20 mL), then washed with a saturated solution of sodiumbicarbonate (10 mL). The aqueous layer was further extracted withdichloromethane (3×15 mL). The combined organics were dried (Na₂SO₄),filtered and concentrated. The crude material was purified by columnchromatography (silica gel, 89:10:1dichloromethane/methanol/concentrated ammonium hydroxide) to afford(S)-N-(1-azabicyclo[2.2.2]oct-3-yl)-6-chloro-2-thiophen-2-ylbenzoxazole-4-carboxamide(30 mg, 31%) as a white solid: ¹H NMR (500 MHz, CDCl₃) δ 9.40 (d, J=7.5Hz, 1H), 8.16 (d, J=2.0 Hz, 1H), 7.94 (dd, J=4.0, 1.5 Hz, 1H), 7.67-7.65(m, 2H), 7.26-7.23 (m, 1H), 4.30-4.26 (m, 1H), 3.49 (ddd, J=11.5, 9.5,2.0 Hz, 1H), 3.15-2.85 (m, 4H), 2.77 (dd, J=14.5, 3.5 Hz, 1H), 2.15-2.05(m, 2H), 1.78-1.70 (m, 2H), 1.65-1.53 (m, 1H); MS (ESI+) m/z 388 (M+H);HPLC >99% (AUC), t_(R)=13.84 min.

Example 112 Preparation of(S)-N-(1-Azabicyclo[2.2.2]oct-3-yl)-2-thiophen-3-ylbenzoxazole-4-carboxamide

Step A: To a suspension of 2-amino-3-hydroxybenzoic acid hydrobromide(152 mg, 0.65 mmol) in dichloromethane (15 mL) was added pyridine (0.42mL, 11.8 mmol) followed by 3-thiophenecarbonyl chloride (286 mg, 1.95mmol). The resulting reaction mixture was stirred at room temperaturefor 15 min then DMAP (40 mg, 0.33 mmol) was added and the reactionmixture was stirred at room temperature overnight. Water (10 mL) wasadded and the reaction stirred for 10 min. The reaction was quenchedwith aqueous 1 N HCl (30 mL) until the solution reached pH 1. Thesolution was stirred for 30 min. The aqueous layer was extracted withethyl acetate. The organic layers were washed with water and brine,dried over Na₂SO₄, filtered and concentrated to a pale orange solid. Theamide product was directly re-dissolved in toluene (10 mL) and thesolution was treated with p-toluenesulfonic acid monohydrate (243 mg,1.28 mmol). The reaction mixture was then heated to reflux overnight.The reaction was cooled down to room temperature, poured into water andextracted with ethyl acetate. The organic layer was separated thenwashed with water, brine, dried over Na₂SO₄, filtered and concentratedto an orange solid. The crude product was purified by columnchromatography (silica gel, 9:1 to 2:1 ethyl acetate/methanol) to affordthe desired product (154 mg, quantitative) as a white solid: MS (ESI+)m/z 246 (M+H).

Step B: A mixture of 2-thiophen-3-ylbenzoxazole-4-carboxylic acid fromStep A (78 mg, 0.32 mmol), (S)-3-aminoquinuclidine dihydrochloride (76mg, 0.38 mmol), 1-ethyl-3-(3-dimethylaminopropyl)carbodiimidehydrochloride (86 mg, 0.45 mmol) and 1-hydroxybenzotriazole (122 mg,0.90 mmol) in DMF (5 mL) was stirred for 10 min at room temperature,then DIPEA (0.26 mL, 1.60 mmol) was added. The resulting reactionmixture was stirred at room temperature overnight. The mixture wasdiluted with ethyl acetate (20 mL), and then washed with a saturatedsolution of sodium bicarbonate. The aqueous layer was further extractedwith ethyl acetate (2×50 mL). The combined organics were dried (Na₂SO₄),filtered and concentrated. The crude material was purified by columnchromatography (silica gel, 90:9:1 ethyl acetate/methanol/concentratedammonium hydroxide) and then recrystallized from acetonitrile to afford(S)-N-(1-azabicyclo[2.2.2]oct-3-yl)-2-thiophen-3-ylbenzoxazole-4-carboxamide(92 mg, 82%) as an off-white solid: ¹H NMR (500 MHz, CDCl₃) δ 9.54 (d,J=7.0 Hz, 1H), 8.23 (dd, J=3.0, 1.0 Hz, 1H), 8.19 (dd, J=8.0, 1.0 Hz,1H), 7.75 (dd, J=6.5, 1.0 Hz, 1H), 7.69 (dd, J=9.0, 1.0 Hz, 1H), 7.51(dd, J=8.0, 3.0 Hz, 1H), 7.46 (t, J=8.0 Hz, 1H), 4.32-4.28 (m, 1H),3.53-3.48 (m, 1H), 3.11-2.99 (m, 2H), 2.92-2.85 (m, 2H), 2.80 (dd,J=14.0, 4.0 Hz, 1H), 2.14-2.12 (m, 1H), 2.09-2.05 (m, 2H), 1.78-1.74 (m,2H); MS (ESI+) m/z 354 (M+H); HPLC >99% (AUC), t_(R)=12.89 min.

Example 113 Preparation ofN-(9-Methyl-9-azabicyclo[3.3.1]non-3-yl)-2-thiophen-3-ylbenzoxazole-4-carboxamide

A mixture of 2-thiophen-3-ylbenzoxazole-4-carboxylic acid (78 mg, 0.32mmol), 3-amino-9-methyl-9-azabicyclo[3.3.1]nonane dihydrochloride (86mg, 0.38 mmol), 1-ethyl-3-(3-dimethylaminopropyl)carbodiimidehydrochloride (86 mg, 0.45 mmol) and 1-hydroxybenzotriazole (122 mg,0.90 mmol) in DMF (5 mL) was stirred for 10 min at room temperature,then DIPEA (0.26 mL, 1.6 mmol) was added. The resulting reaction mixturewas stirred at room temperature overnight. The mixture was diluted withethyl acetate (20 mL), and then washed with a saturated solution ofsodium bicarbonate. The aqueous layer was further extracted with ethylacetate (2×50 mL). The combined organics were dried (Na₂SO₄), filteredand concentrated. The crude material was purified by columnchromatography (silica gel, 90:9:1 ethyl acetate/methanol/concentratedammonium hydroxide) and then recrystallized from acetonitrile to affordN-(9-methyl-9-azabicyclo[3.3.1]non-3-yl)-2-thiophen-3-ylbenzoxazole-4-carboxamide(51 mg, 41%) as an off-white solid: ¹H NMR (500 MHz, CDCl₃) δ 8.99 (d,J=7.0 Hz, 1H), 8.24 (d, J=1.5 Hz, 1H), 8.20 (d, J=7.5 Hz, 1H), 7.78 (d,J=5.0 Hz, 1H), 7.77 (d, J=7.5 Hz, 1H), 7.52-7.51 (m, 1H), 7.44 (t, J=7.5Hz, 1H), 4.61-4.51 (m, 1H), 3.19-3.01 (m, 2H), 2.72-2.61 (m, 2H), 2.54(s, 3H), 2.22-1.98 (m, 2H), 1.60-1.47 (m, 4H), 1.26-1.13 (m, 2H); MS(ESI+) m/z 382 (M+H); HPLC >99% (AUC), t_(R)=13.40 min.

Example 114 Preparation ofN-(9-Methyl-3-oxa-9-azabicyclo[3.3.1]non-7-yl)-6-chloro-2-thiophen-3-ylbenzoxazole-4-carboxamide

Step A: To a mixture of 2-amino-5-chloro-3-hydroxybenzoic acidhydrobromide (0.40 g, 1.49 mmol) and 3-thiophenecarbonyl chloride (219mg, 1.49 mmol) in dichloromethane (10 mL) was added triethylamine (0.84mL, 5.96 mmol) dropwise, then the reaction mixture was stirred at roomtemperature for 12 h. The reaction mixture was diluted withdichloromethane, and then washed with 2 N HCl. The aqueous layer wasextracted with dichloromethane. The combined organic layers were washedwith brine, dried (Na₂SO₄), filtered and concentrated. The crude productwas dissolved in toluene (10 mL) and the solution was treated withp-toluenesulfonic acid monohydrate (230 mg, 1.21 mmol). The reactionmixture was then heated to reflux for 2 h. The reaction was cooled downto room temperature, poured into water and extracted with ethyl acetate.The organic layer was separated then washed with water, brine, dried(Na₂SO₄), filtered and concentrated. The crude product was purified bycolumn chromatography (silica gel, 9:1 to 3:1 ethyl acetate/methanol) toafford the desired product (0.28 g, 67%) as a yellow solid: ¹H NMR (500MHz, DMSO-d₆) δ 8.53 (s, 1H), 7.94 (s, 1H), 7.82 (dd, J=5.0, 3.0 Hz,1H), 7.78 (d, J=5.0 Hz, 1H), 7.74 (s, 1H); MS (ESI+) m/z 279 (M+H).

Step B: A mixture of benzoxazole carboxylic acid from Step A (70 mg,0.25 mmol), 9-methyl-3-oxa-9-azabicyclo[3.3.1]non-7-ylaminedihydrochloride (57 mg, 0.25 mmol),1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (96 mg, 0.50mmol) and 1-hydroxybenzotriazole (68 mg, 0.50 mmol) in DMF (2 mL) wasstirred at room temperature for 5 min, then triethylamine (0.13 mL, 1.0mmol) was added. The resulting reaction mixture was stirred at roomtemperature for 12 h. The mixture was diluted with dichloromethane (20mL), then washed with a saturated solution of sodium bicarbonate (10mL). The aqueous layer was further extracted with dichloromethane (3×15mL). The combined organics were dried (Na₂SO₄), filtered andconcentrated. The crude material was purified by column chromatography(silica gel, 89:10:1 dichloromethane/methanol/concentrated ammoniumhydroxide) followed by recrystallization from ethyl acetate to affordN-(9-methyl-3-oxa-9-azabicyclo[3.3.1]non-7-yl)-6-chloro-2-thiophen-3-ylbenzoxazole-4-carboxamide(25 mg, 24%) as an off-white solid: ¹H NMR (500 MHz, CDCl₃) δ 10.18 (d,J=9.5 Hz, 1H), 8.31 (dd, J=3.0, 1.0 Hz, 1H), 8.17 (d, J=3.0 Hz, 1H),7.84 (dd, J=5.0, 1.0 Hz, 1H), 7.64 (d, J=2.0 Hz, 1H), 7.48 (dd, J=5.0,3.0 Hz, 1H), 4.94-4.88 (m, 1H), 4.08 (d, J=11.0 Hz, 2H), 3.93 (d, J=11.0Hz, 2H), 2.72 (s, 2H), 2.61-2.54 (m, 5H), 1.58 (s, 2H); MS (ESI+) m/z418 (M+H); HPLC 98.1% (AUC), t_(R)=13.22 min.

Example 115 Preparation ofN-(9-Methyl-9-azabicyclo[3.3.1]non-3-yl)-6-chloro-2-thiophen-3-ylbenzoxazole-4-carboxamide

A mixture of 6-chloro-2-(thiophen-3-yl)benzo[d]oxazole-4-carboxylic acid(70 mg, 0.25 mmol), 3-amino-9-methyl-9-azabicyclo[3.3.1]nonanedihydrochloride (57 mg, 0.25 mmol),1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (96 mg, 0.50mmol) and 1-hydroxybenzotriazole (68 mg, 0.50 mmol) in DMF (2 mL) wasstirred at room temperature for 5 min, then triethylamine (0.13 mL, 1.0mmol) was added. The resulting reaction mixture was stirred at roomtemperature for 12 h. The mixture was diluted with dichloromethane (20mL), then washed with a saturated solution of sodium bicarbonate (10mL). The aqueous layer was further extracted with dichloromethane (3×15mL). The combined organics were dried (Na₂SO₄), filtered andconcentrated. The crude material was purified by column chromatography(silica gel, 89:10:1 dichloromethane/methanol/concentrated ammoniumhydroxide) followed by recrystallization from acetonitrile to affordN-(9-methyl-9-azabicyclo[3.3.1]non-3-yl)-6-chloro-2-thiophen-3-ylbenzoxazole-4-carboxamide(30 mg, 29%) as a white solid: ¹H NMR (500 MHz, CDCl₃) δ 8.85 (d, J=7.5Hz, 1H), 8.25 (dd, J=3.0, 1.5 Hz, 1H), 8.19 (d, J=2.0 Hz, 1H), 7.75 (dd,J=5.0, 1.5 Hz, 1H), 7.66 (d, J=2.0 Hz, 1H), 7.52 (dd, J=5.5, 3.0 Hz,1H), 4.60-4.53 (m, 1H), 3.12 (d, J=10.5 Hz, 2H), 2.65-2.58 (m, 2H), 2.53(s, 3H), 2.12-1.95 (m, 3H), 1.60-1.52 (m, 1H), 1.49-1.43 (m, 2H), 1.14(d, J=12.5 Hz, 2H); MS (ESI+) m/z 416 (M+H); HPLC 98.2% (AUC),t_(R)=12.82 min.

Example 116 Preparation of(S)-N-(1-Azabicyclo[2.2.2]oct-3-yl)-6-chloro-2-thiophen-3-ylbenzoxazole-4-carboxamide

A mixture of 6-chloro-2-(thiophen-3-yl)benzo[d]oxazole-4-carboxylic acid(70 mg, 0.25 mmol), (S)-(−)-3-aminoquinuclidine dihydrochloride (50 mg,0.25 mmol), 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride(96 mg, 0.50 mmol) and 1-hydroxybenzotriazole (68 mg, 0.50 mmol) in DMF(2 mL) was stirred at room temperature for 5 min, then triethylamine(0.13 mL, 1.0 mmol) was added. The resulting reaction mixture wasstirred at room temperature for 12 h. The mixture was diluted withdichloromethane (20 mL), then washed with a saturated solution of sodiumbicarbonate (10 mL). The aqueous layer was further extracted withdichloromethane (3×20 mL). The combined organics were dried (Na₂SO₄),filtered and concentrated. The crude material was purified by columnchromatography (silica gel, 89:10:1dichloromethane/methanol/concentrated ammonium hydroxide) followed byrecrystallization from acetonitrile to afford(S)-N-(1-azabicyclo[2.2.2]oct-3-yl)-6-chloro-2-thiophen-3-ylbenzoxazole-4-carboxamide(17 mg, 18%) as a colorless crystal: ¹H NMR (500 MHz, CDCl₃) δ 9.41 (d,J=7.5 Hz, 1H), 8.23 (dd, J=3.0, 1.5 Hz, 1H), 8.16 (d, J=2.0 Hz, 1H),7.73 (dd, J=5.0, 1.0 Hz, 1H), 7.68 (d, J=2.0 Hz, 1H), 7.52 (dd, J=5.0,3.0 Hz, 1H), 4.29-4.25 (m, 1H), 3.49 (ddd, J=11.5, 9.5, 2.0 Hz, 1H),3.10-2.83 (m, 4H), 2.77 (dd, J=14.0, 4.5 Hz, 1H), 2.15-2.11 (m, 1H),2.04-1.98 (m, 1H), 1.78-1.70 (m, 2H), 1.60-1.51 (m, 1H); MS (ESI+) m/z388 (M+H); HPLC >99% (AUC), t_(R)=12.45 min.

Example 117 Preparation of(S)-N-(1-Azabicyclo[2.2.2]oct-3-yl)-2-benzo[b]thiophen-2-ylbenzoxazole-4-carboxamide

Step A: To a suspension of 2-amino-3-hydroxybenzoic acid hydrobromide(152 mg, 0.65 mmol) in dichloromethane (15 mL) was added pyridine (0.42mL, 5.2 mmol) followed by thianaphthene-2-carbonyl chloride (384 mg,1.95 mmol). The resulting reaction mixture was stirred at roomtemperature for 15 min, then DMAP (16 mg, 0.13 mmol) was added and thereaction mixture was stirred at room temperature overnight. Water (10mL) was added and the reaction was stirred for 10 min. The reaction wasquenched with aqueous 1 N HCl (20 mL) until the solution reached pH 1.The solution was stirred for 30 min. The aqueous layer was extractedwith ethyl acetate. The organic layers were washed with brine and driedover Na₂SO₄, filtered and concentrated to a yellow solid. The productwas directly re-dissolved in toluene (10 mL) and the solution wastreated with p-toluenesulfonic acid monohydrate (234 mg, 1.23 mmol). Thereaction mixture was then heated to reflux overnight. The reaction wascooled down to room temperature, poured into water and extracted withethyl acetate. The organic layer was separated then washed with water,brine, dried over Na₂SO₄, filtered and concentrated to a yellow solid.The crude product was purified by column chromatography (silica gel, 9:1to 2:1 ethyl acetate/methanol) to afford the desired product (256 mg,quantitative) as a pale yellow solid: ¹H NMR (300 MHz, DMSO-d₆) δ 8.42(s, 1H), 8.13-8.02 (m, 1H), 7.87-7.74 (m, 2H), 7.57-7.46 (m, 2H), 7.40(t, J=15.0 Hz, 1H), 7.32-7.28 (m, 1H); MS (ESI+) m/z 296 (M+H).

Step B: A mixture of 2-benzo[b]thiophen-2-ylbenzoxazole-4-carboxylicacid from Step A (128 mg, 0.43 mmol), (S)-3-aminoquinuclidinedihydrochloride (104 mg, 0.52 mmol),1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (164 mg,0.86 mmol) and 1-hydroxybenzotriazole (116 mg, 0.86 mmol) in DMF (5 mL)was stirred for 10 min at room temperature, then triethylamine (0.63 mL,2.2 mmol) was added. The resulting reaction mixture was stirred at roomtemperature overnight. The mixture was diluted with ethyl acetate (20mL), and then washed with a saturated solution of sodium bicarbonate.The aqueous layer was further extracted with ethyl acetate (2×50 mL).The combined organics were dried (Na₂SO₄), filtered and concentrated.The crude material was purified by column chromatography (silica gel,90:9:1 ethyl acetate/methanol/concentrated ammonium hydroxide) to afford(S)-N-(1-azabicyclo[2.2.2]oct-3-yl)-2-benzo[b]thiophen-2-ylbenzoxazole-4-carboxamide(42 mg, 24%) as a white solid: ¹H NMR (500 MHz, CDCl₃) δ 9.52 (d, J=7.5Hz, 1H), 8.26-8.18 (m, 2H), 7.95-7.92 (m, 2H), 7.72 (dd, J=7.0, 1.0 Hz,1H), 7.52-7.45 (m, 3H), 7.44 (t, J=8.0 Hz, 1H), 4.34-4.29 (m, 1H),3.55-3.49 (m, 1H), 3.21-3.04 (m, 2H), 2.96-2.82 (m, 3H), 2.18-2.12 (m,2H), 1.81-1.63 (m, 2H); MS (ESI+) m/z 404 (M+H); HPLC >99% (AUC),t_(R)=13.10 min.

Example 118 Preparation ofN-(9-Methyl-9-azabicyclo[3.3.1]non-3-yl)-2-benzo[b]thiophen-2-ylbenzoxazole-4-carboxamide

A mixture of 2-benzo[b]thiophen-2-ylbenzoxazole-4-carboxylic acid (128mg, 0.43 mmol), 3-amino-9-methyl-9-azabicyclo[3.3.1]nonanedihydrochloride (118 mg, 0.52 mmol),1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (164 mg,0.86 mmol) and 1-hydroxybenzotriazole (116 mg, 0.86 mmol) in DMF (5 mL)was stirred for 10 min at room temperature, then triethylamine (0.63 mL,2.2 mmol) was added. The resulting reaction mixture was stirred at roomtemperature overnight. The mixture was diluted with ethyl acetate (20mL), and then washed with a saturated solution of sodium bicarbonate.The aqueous layer was further extracted with ethyl acetate (2×50 mL).The combined organics were dried (Na₂SO₄), filtered and concentrated.The crude material was purified by column chromatography (silica gel,90:9:1 ethyl acetate/methanol/concentrated ammonium hydroxide) to affordN-(9-methyl-9-azabicyclo[3.3.1]non-3-yl)-2-benzo[b]thiophen-2-ylbenzoxazole-4-carboxamide (49 mg, 61%) as an off-white solid: ¹H NMR(500 MHz, CDCl₃) δ 8.97 (d, J=7.0 Hz, 1H), 8.38-8.19 (m, 2H), 7.95 (dd,J=7.5, 1.5 Hz, 2H), 7.71 (dd, J=8.0, 1.0 Hz, 1H), 7.51-7.46 (m, 3H),4.63-4.55 (m, 1H), 3.14 (d, J=10.0 Hz, 2H), 2.70-2.62 (m, 2H), 2.56 (s,3H), 2.08-2.00 (m, 2H), 1.66-1.52 (m, 4H), 1.28-1.22 (m, 2H); MS (ESI+)m/z 432 (M+H); HPLC >99% (AUC), t_(R)=14.59 min.

Example 119 Preparation of(S)-N-(1-Azabicyclo[2.2.2]oct-3-yl)-2-benzofuran-2-ylbenzoxazole-4-carboxamide0

Step A: To a suspension of 2-amino-3-hydroxybenzoic acid hydrobromide(152 mg, 0.65 mmol) in dichloromethane (15 mL) was added pyridine (0.42mL, 5.2 mmol) followed by benzofuran-2-carbonyl chloride (352 mg, 1.95mmol). The resulting reaction mixture was stirred at room temperaturefor 15 min, then DMAP (16 mg, 0.13 mmol) was added and the reactionmixture was stirred at room temperature overnight. Water (10 mL) wasadded and the reaction was stirred for 10 min. The reaction was quenchedwith aqueous 1 N HCl (20 mL) until the solution reached pH 1. Thesolution was stirred for 30 min. The aqueous layer was extracted withethyl acetate. The organic layers were washed with brine and dried overNa₂SO₄, filtered and concentrated to a yellow solid. The product wasdirectly re-dissolved in toluene (10 mL) and the solution was treatedwith p-toluenesulfonic acid monohydrate (240 mg, 1.26 mmol). Thereaction mixture was then heated to reflux overnight. The reaction wascooled down to room temperature, poured into water and extracted withethyl acetate. The organic layer was separated then washed with water,brine, dried over Na₂SO₄, filtered and concentrated to a yellow solid.The crude product was purified by column chromatography (silica gel, 9:1to 2:1 ethyl acetate/methanol) to afford the desired product (337 mg,quantitative) as a yellow solid: ¹H NMR (500 MHz, DMSO-d₆) δ 8.09-8.03(m, 1H), 7.89-7.84 (m, 1H), 7.63-7.59 (m, 1H), 7.55-7.44 (m, 2H),7.33-7.27 (m, 1H), 7.23-7.17 (m, 1H), 7.05 (s, 1H); MS (ESI+) m/z 280(M+H).

Step B: A mixture of 2-benzofuran-2-ylbenzoxazole-4-carboxylic acid fromStep A (168 mg, 0.60 mmol), (S)-3-aminoquinuclidine dihydrochloride (143mg, 0.72 mmol), 1-ethyl-3-(3-dimethylaminopropyl)carbodiimidehydrochloride (229 mg, 1.20 mmol) and 1-hydroxybenzotriazole (162 mg,1.20 mmol) in DMF (5 mL) was stirred for 10 min at room temperature,then triethylamine (0.39 mL, 3.0 mmol) was added. The resulting reactionmixture was stirred at room temperature overnight. The mixture wasdiluted with ethyl acetate (20 mL), and then washed with a saturatedsolution of sodium bicarbonate. The aqueous layer was further extractedwith ethyl acetate (2×50 mL). The combined organics were dried (Na₂SO₄),filtered and concentrated. The crude material was purified by columnchromatography (silica gel, 90:9:1 ethyl acetate/methanol/concentratedammonium hydroxide) to afford the desired product (157 mg, 68%) as anoff-white solid which was purified again by semi-preparative HPLC andrecrystallization from ethyl acetate to give(S)-N-(1-azabicyclo[2.2.2]oct-3-yl)-2-benzofuran-2-ylbenzoxazole-4-carboxamide:¹H NMR (500 MHz, CDCl₃) δ 9.52 (d, J=7.0 Hz, 1H), 8.24 (dd, J=8.0, 1.0Hz, 1H), 7.76 (dd, J=8.0, 1.5 Hz, 2H), 7.69-7.64 (m, 2H), 7.55-7.48 (m,2H), 7.39-7.35 (m, 1H), 4.35-4.29 (m, 1H), 3.55-3.49 (m, 1H), 3.20-3.03(m, 2H), 2.97-2.84 (m, 3H), 2.19-2.10 (m, 2H), 1.81-1.63 (m, 3H); MS(ESI+) m/z 388 (M+H); HPLC >99% (AUC), t_(R)=12.90 min.

Example 120 Preparation ofN-(9-Methyl-9-azabicyclo[3.3.1]non-3-yl)-2-benzofuran-2-ylbenzoxazole-4-carboxamide

A mixture of 2-benzofuran-2-ylbenzoxazole-4-carboxylic acid (168 mg,0.60 mmol), 3-amino-9-methyl-9-azabicyclo[3.3.1]nonane dihydrochloride(163 mg, 0.72 mmol), 1-ethyl-3-(3-dimethylaminopropyl)carbodiimidehydrochloride (229 mg, 1.20 mmol) and 1-hydroxybenzotriazole (162 mg,1.20 mmol) in DMF (5 mL) was stirred for 10 min at room temperature,then triethylamine (0.39 mL, 3.0 mmol) was added. The resulting reactionmixture was stirred at room temperature overnight. The mixture wasdiluted with ethyl acetate (20 mL), and then washed with a saturatedsolution of sodium bicarbonate. The aqueous layer was further extractedwith ethyl acetate (2×50 mL). The combined organics were dried (Na₂SO₄),filtered and concentrated. The crude material was purified bysemi-preparative HPLC to affordN-(9-methyl-9-azabicyclo[3.3.1]non-3-yl)-2-benzofuran-2-ylbenzoxazole-4-carboxamide(22 mg, 9%) as an off-white solid: ¹H NMR (500 MHz, CDCl₃) δ 9.00-8.95(m, 1H), 8.26 (dd, J=7.5, 1.0 Hz, 1H), 7.78-7.66 (m, 4H), 7.53-7.47 (m,2H), 7.38 (t, J=7.5 Hz, 1H), 4.65-4.58 (m, 1H), 3.23-3.12 (m, 2H),2.71-2.63 (m, 2H), 2.58 (s, 3H), 2.21-2.00 (m, 3H), 1.68-1.52 (m, 3H),1.32-1.22 (m, 2H); MS (ESI+) m/z 416 (M+H); HPLC >99% (AUC), t_(R)=13.43min.

Example 121 Preparation of(S)-N-(1-Azabicyclo[2.2.2]oct-3-yl)-2-(3-methylthiophen-2-yl)benzoxazole-4-carboxamide

Step A: To a suspension of 2-amino-3-hydroxybenzoic-acid hydrobromide(314 mg, 1.34 mmol) in dichloromethane (10 mL) was added3-methylthiophene-2-carbonyl chloride (215 mg, 1.34 mmol). The resultingreaction mixture was stirred at room temperature for 10 min, thentriethylamine (0.70 mL, 5.40 mmol) was added and the reaction mixturewas stirred at room temperature overnight. The reaction was quenchedwith aqueous 1 N HCl (25 mL) until the solution reached pH 1. Thesolution was stirred for 30 min. The aqueous layer was extracted withethyl acetate. The organic layers were washed with water and brine,dried over Na₂SO₄, filtered and concentrated to an orange solid. Theamide product was directly re-dissolved in toluene (10 mL) and thesolution was treated with p-toluenesulfonic acid monohydrate (336 mg,1.77 mmol). The reaction mixture was then heated to reflux overnight.The reaction was cooled down to room temperature, poured into water andextracted with ethyl acetate. The organic layer was separated thenwashed with water, brine, dried over Na₂SO₄, filtered and concentratedto an orange solid. The crude product was purified by columnchromatography (silica gel, 9:1 to 3:1 ethyl acetate/methanol) to affordthe desired product (200 mg, 65%) as an orange solid: ¹H NMR (500 MHz,CD₃OD) δ 7.94 (dd, J=8.0, 1.0 Hz, 1H), 7.81 (dd, J=8.5, 1.0 Hz, 1H),7.65 (d, J=5.0 Hz, 1H), 7.44 (t, J=8.0 Hz, 1H), 7.08 (d, J=5.0 Hz, 1H),2.74 (s, 3H); MS (ESI+) m/z 260 (M+H).

Step B: A mixture of 2-(3-methylthiophen-2-yl)benzoxazole-4-carboxylicacid from Step A (87 mg, 0.34 mmol), (S)-3-aminoquinuclidinedihydrochloride (82 mg, 0.41 mmol),1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (130 mg,0.68 mmol) and 1-hydroxybenzotriazole (92 mg, 0.68 mmol) in DMF (5 mL)was stirred at room temperature for 10 min, then triethylamine (0.24 mL,1.70 mmol) was added. The resulting reaction mixture was stirred at roomtemperature overnight. The mixture was diluted with dichloromethane (20mL), and then washed with a saturated solution of sodium bicarbonate.The aqueous layer was further extracted with dichloromethane (2×50 mL).The combined organics were dried (Na₂SO₄), filtered and concentrated.The crude material was purified by column chromatography (silica gel,90:9:1 ethyl acetate/methanol/concentrated ammonium hydroxide) to afford(S)-N-(1-azabicyclo[2.2.2]oct-3-yl)-2-(3-methylthiophen-2-yl)benzoxazole-4-carboxamide(87 mg, 70%) as a white solid: ¹H NMR (500 MHz, CDCl₃) δ 9.41 (d, J=7.0Hz, 1H), 8.18 (dd, J=7.5, 1.0 Hz, 1H), 7.68 (dd, J=8.0, 1.0 Hz, 1H),7.51 (d, J=5.0 Hz, 1H), 7.44 (t, J=8.0 Hz, 1H), 7.05 (d, J=5.0 Hz, 1H),4.34-4.27 (m, 1H), 3.08-2.88 (m, 4H), 2.79-2.76 (m, 4H), 2.15-2.11 (m,1H), 1.79-1.55 (m, 5H); MS (ESI+) m/z 368 (M+H); HPLC >99% (AUC),t_(R)=12.33 min.

Example 122 Preparation ofN-(9-Methyl-9-azabicyclo[3.3.1]non-3-yl)-2-(3-methylthiophen-2-yl)benzoxazole-4-carboxamide

A mixture of 2-(3-methylthiophen-2-yl)benzoxazole-4-carboxylic acid (87mg, 0.34 mmol), 3-amino-9-methyl-9-azabicyclo[3.3.1]nonanedihydrochloride (93 mg, 0.41 mmol),1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (130 mg,0.68 mmol) and 1-hydroxybenzotriazole (92 mg, 0.68 mmol) in DMF (5 mL)was stirred at room temperature for 10 min, then triethylamine (0.24 mL,1.7 mmol) was added. The resulting reaction mixture was stirred at roomtemperature overnight. The mixture was diluted with dichloromethane (30mL), and then washed with a saturated solution of sodium bicarbonate.The aqueous layer was further extracted with dichloromethane (2×30 mL).The combined organics were dried (Na₂SO₄), filtered and concentrated.The crude material was purified by column chromatography (silica gel,90:9:1 ethyl acetate/methanol/concentrated ammonium hydroxide) to affordN-(9-methyl-9-azabicyclo[3.3.1]non-3-yl)-2-(3-methylthiophen-2-yl)benzoxazole-4-carboxamide(92 mg, 69%) as an off-white solid: ¹H NMR (500 MHz, CDCl₃) δ 8.99 (d,J=7.0 Hz, 1H), 8.19 (dd, J=8.0, 1.0 Hz, 1H), 7.66 (dd, J=8.5, 1.0 Hz,1H), 7.51 (d, J=5.0 Hz, 1H), 7.43 (t, J=7.5 Hz, 1H), 7.06 (d, J=5.0 Hz,1H), 4.55-4.51 (m, 1H), 3.18-3.09 (m, 2H), 2.79 (s, 3H), 2.68-2.60 (m,2H), 2.55 (s, 3H), 2.08-1.98 (m, 3H), 1.65-1.42 (m, 3H), 1.16-1.11 (m,2H); MS (ESI+) m/z 396 (M+H); HPLC=98.4% (AUC), t_(R)=12.84 min.

Example 123 Preparation ofN-(9-Methyl-9-azabicyclo[3.3.1]non-3-yl)-6-chloro-2-(3′-methylthiophen-2-yl)benzoxazole-4-carboxamide

Step A: To a suspension of 2-amino-3-hydroxybenzoic acid hydrobromide(359 mg, 1.34 mmol) in dichloromethane (10 mL) was added3-methylthiophene-2-carbonyl chloride (215 mg, 1.34 mmol). The resultingreaction mixture was stirred at room temperature for 10 min thentriethylamine (0.70 mL, 5.40 mmol) was added and the reaction mixturewas stirred at room temperature overnight. The reaction was quenchedwith aqueous 1 N HCl (25 mL) until the solution reached pH 1. Thesolution was stirred for 30 min. The aqueous layer was extracted withethyl acetate. The organic layers were washed with water and brine,dried over Na₂SO₄, filtered and concentrated to a yellow solid. Theamide product was directly re-dissolved in toluene (10 mL) and thesolution was treated with p-toluenesulfonic acid monohydrate (382 mg,2.01 mmol). The reaction mixture was then heated to reflux overnight.The reaction was cooled down to room temperature, poured into water andextracted with ethyl acetate. The organic layer was separated thenwashed with water, brine, dried over Na₂SO₄, filtered and concentratedto an orange solid. The crude product was purified by columnchromatography (silica gel, 9:1 to 2:1 ethyl acetate/methanol) to affordthe desired product (243 mg, 62%) as an orange solid: ¹H NMR (300 MHz,DMSO-d₆) δ 7.90 (d, J=1.5 Hz, 1H), 7.84 (d, J=5.1 Hz, 1H), 7.62 (s, 1H),7.16 (d, J=5.1 Hz, 1H), 2.68 (s, 3H); MS (ESI+) m/z 293 (M+H).

Step B: A mixture of6-chloro-2-(3-methylthiophen-2-yl)benzoxazole-4-carboxylic acid fromstep A (89 mg, 0.31 mmol), 3-amino-9-methyl-9-azabicyclo[3.3.1]nonanedihydrochloride (84 mg, 0.37 mmol),1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (118 mg,0.62 mmol) and 1-hydroxybenzotriazole (84 mg, 0.62 mmol) in DMF (3 mL)was stirred at room temperature for 10 min, then triethylamine (0.22 mL,1.6 mmol) was added. The resulting reaction mixture was stirred at roomtemperature overnight. The mixture was diluted with dichloromethane (100mL), and then washed with a saturated solution of sodium bicarbonate.The aqueous layer was further extracted with dichloromethane (2×100 mL).The combined organics were dried (Na₂SO₄), filtered and concentrated.The crude material was purified by column chromatography (silica gel,90:9:1 ethyl acetate/methanol/concentrated ammonium hydroxide) andsemi-preparative HPLC to affordN-(9-methyl-9-azabicyclo[3.3.1]non-3-yl)-6-chloro-2-(3-methylthiophen-2-yl)benzoxazole-4-carboxamide(18 mg, 14%) as a white solid: ¹H NMR (500 MHz, CDCl₃) δ 8.94 (d, J=6.5Hz, 1H), 8.17 (d, J=2.0 Hz, 1H), 7.66 (d, J=2.0 Hz, 1H), 7.53 (d, J=5.0Hz, 1H), 7.06 (d, J=5.0 Hz, 1H), 4.62-4.54 (m, 1H), 3.17-3.13 (m, 2H),2.77 (s, 3H), 2.68-2.59 (m, 2H), 2.55 (s, 3H), 2.07-1.99 (m, 3H),1.60-1.43 (m, 3H), 1.17-1.11 (m, 2H); MS (ESI+) m/z 430 (M+H);HPLC >99.0% (AUC), t_(R)=13.50 min.

Example 124 Preparation of(S)-N-(1-Azabicyclo[2.2.2]oct-3-yl)-2-(3-chlorothiophen-2-yl)benzoxazole-4-carboxamide

Step A: To an ice-cold solution of 3-chlorothiophene-2-carboxylic acid(218 mg, 1.34 mmol) in dichloromethane (10 mL) was added oxalyl chloride(0.11 mL, 1.34 mmol) dropwise. The ice bath was removed and stirringcontinued for 1 h. 2-Amino-3-hydroxybenzoic acid hydrobromide (314 mg,1.34 mmol) was added followed by triethylamine (0.75 mL, 5.4 mmol). Theresulting reaction mixture was stirred at room temperature overnight.The reaction was quenched with aqueous 1 N HCl (25 mL) until thesolution reached pH 1 and stirred for 30 min. The aqueous layer wasextracted with ethyl acetate. The organic layers were washed with brineand dried over Na₂SO₄, filtered and concentrated to a yellow solid. Theproduct was directly re-dissolved in toluene (10 mL) and the solutionwas treated with p-toluenesulfonic acid monohydrate (447 mg, 2.36 mmol).The reaction mixture was then heated to reflux overnight. The reactionwas cooled down to room temperature, poured into water and extractedwith ethyl acetate. The organic layer was separated then washed withwater, brine, dried over Na₂SO₄, filtered and concentrated to a yellowsolid. The crude product was purified by column chromatography (silicagel, 9:1 to 2:1 ethyl acetate/methanol) to afford the desired product(108 mg, 25%) as a yellow solid: ¹H NMR (500 MHz, DMSO-d₆) δ 8.05 (d,J=5.0 Hz, 1H), 7.83 (d, J=8.0 Hz, 1H), 7.79 (d, J=7.5 Hz, 1H), 7.42 (t,J=7.5 Hz, 1H), 7.34 (d, J=5.5 Hz, 1H); MS (ESI+) m/z 280 (M+H).

Step B: A mixture of 2-(3-chlorothiophen-2-yl)benzoxazole-4-carboxylicacid from Step A (59 mg, 0.21 mmol), (S)-3-aminoquinuclidinedihydrochloride (50 mg, 0.251 mmol),1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (80 mg, 0.42mmol) and 1-hydroxybenzotriazole (57 mg, 0.42 mmol) in DMF (2 mL) wasstirred at room temperature for 10 min, then triethylamine (0.15 mL,1.05 mmol) was added. The resulting reaction mixture was stirred at roomtemperature overnight. The mixture was diluted with dichoromethane (30mL), and then washed with a saturated solution of sodium bicarbonate.The aqueous layer was further extracted with dichloromethane (2×30 mL).The combined organics were dried (Na₂SO₄), filtered and concentrated.The crude material was purified by column chromatography (silica gel,90:9:1 ethyl acetate/methanol/concentrated ammonium hydroxide) andsemi-preparative HPLC to afford(S)-N-(1-azabicyclo[2.2.2]oct-3-yl)-2-(3-chlorothiophen-2-yl)benzoxazole-4-carboxamide(21 mg, 26%) as a white solid: ¹H NMR (500 MHz, CDCl₃) δ 9.45 (d, J=7.0Hz, 1H), 8.21 (dd, J=8.0, 1.0 Hz, 1H), 7.73 (dd, J=8.0, 1.0 Hz, 1H),7.59 (d, J=5.5 Hz, 1H), 7.50 (t, J=8.0 Hz, 1H), 7.16 (d, J=5.0 Hz, 1H),4.37-4.30 (m, 1H), 3.57-3.49 (m, 1H), 3.14-3.06 (m, 1H), 3.04-2.89 (m,3H), 2.86-2.80 (m, 1H), 2.19-2.05 (m, 2H), 1.83-1.75 (m, 2H) 1.63-1.45(m, 1H); MS (ESI+) m/z 388 (M+H); HPLC 96.5% (AUC), t_(R)=12.57 min.

Example 125 Preparation ofN-(9-Methyl-9-azabicyclo[3.3.1]non-3-yl)-2-(3-chlorothiophen-2-yl)benzoxazole-4-carboxamide

A mixture of 2-(3-chlorothiophen-2-yl)benzoxazole-4-carboxylic acid (59mg, 0.21 mmol), 3-amino-9-methyl-9-azabicyclo[3.3.1]nonanedihydrochloride (57 mg, 0.25 mmol),1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (80 mg, 0.42mmol) and 1-hydroxybenzotriazole (57 mg, 0.42 mmol) in DMF (2 mL) wasstirred at room temperature for 10 min, then triethylamine (0.15 mL,1.05 mmol) was added. The resulting reaction mixture was stirred at roomtemperature overnight. The mixture was diluted with dichloromethane (30mL), and then washed with a saturated solution of sodium bicarbonate.The aqueous layer was further extracted with dichloromethane (2×30 mL).The combined organics were dried (Na₂SO₄), filtered and concentrated.The crude material was purified by column chromatography (silica gel,90:9:1 ethyl acetate/methanol/concentrated ammonium hydroxide) andsemi-preparative HPLC to affordN-(9-methyl-9-azabicyclo[3.3.1]non-3-yl)-2-(3-chlorothiophen-2-yl)benzoxazole-4-carboxamide(45 mg, 51%) as a white solid: ¹H NMR (500 MHz, CDCl₃) δ 9.11 (d, J=7.0Hz, 1H), 8.22 (dd, J=8.0, 1.0 Hz, 1H), 7.69 (dd, J=8.0, 1.0 Hz, 1H),7.59 (d, J=5.5 Hz, 1H), 7.48 (t, J=8.0 Hz, 1H), 7.16 (d, J=5.5 Hz, 1H),4.65-4.55 (m, 1H), 3.18-3.09 (m, 2H), 2.68-2.60 (m, 2H) 2.56 (s, 3H),2.12-1.95 (m, 3H), 1.62-1.44 (m, 4H), 1.21-1.10 (m, 1H); MS (ESI+) m/z416 (M+H); HPLC >99% (AUC), t_(R)=12.97 min.

Example 126 Preparation of(S)-N-(1-Azabicyclo[2.2.2]oct-3-yl)-2-(3-bromothiophen-2-yl)benzoxazole-4-carboxamide

Step A: To a suspension of 3-bromothiophene-2-carboxylic acid (500 mg,2.42 mmol) dichloromethane (10 mL) was added oxalyl chloride (0.42 mL,4.84 mmol) dropwise, followed by 2 drops of DMF. The reaction wasstirred at room temperature for 3 h. The solvent was evaporated and thesolid directly redissolved in dichloromethane (10 mL).2-Amino-3-hydroxybenzoic acid hydrobromide (565 mg, 2.42 mmol) was addedto the reaction mixture followed by triethylamine (1.35 mL, 9.68 mmol).The reaction mixture was stirred at room temperature overnight. Thereaction was quenched with aqueous 1 N HCl (20 mL) until the solutionreached pH 1. The solution was stirred for 30 min. The aqueous layer wasextracted with ethyl acetate. The organic layers were washed with brineand dried over Na₂SO₄, filtered and concentrated to an orange solid. Theproduct was directly re-dissolved in toluene (10 mL) and the solutionwas treated with p-toluenesulfonic acid monohydrate (670 mg, 3.53 mmol).The reaction mixture was then heated to reflux for 6 h. The reaction wascooled down to room temperature, poured into water and extracted withethyl acetate. The organic layer was separated then washed with water,brine, dried over Na₂SO₄, filtered and concentrated to an orange solid.The crude product was purified by column chromatography (silica gel, 9:1to 2:1 ethyl acetate/methanol) to afford the desired product (488 mg,64%) as a pale yellow solid: ¹H NMR (500 MHz, DMSO-d₆) δ 8.00 (d, J=5.5Hz, 1H), 7.78 (d, J=8.0 Hz, 1H), 7.74 (d, J=7.5 Hz, 1H), 7.40 (t, J=8.0Hz, 1H), 7.37 (d, J=5.0 Hz, 1H); MS (ESI+) m/z 324 (M+H).

Step B: A mixture of 2-(3-bromothiophen-2-yl)benzoxazole-4-carboxylicacid from Step A (302 mg, 0.93 mmol), (S)-3-aminoquinuclidinedihydrochloride (223 mg, 1.12 mmol),1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (355 mg,1.86 mmol) and 1-hydroxybenzotriazole (251 mg, 1.86 mmol) in DMF (5 mL)was stirred at room temperature for 10 min, then triethylamine (0.65 mL,4.65 mmol) was added. The resulting reaction mixture was stirred at roomtemperature overnight. The mixture was diluted with dichloromethane (30mL), and then washed with a saturated solution of sodium bicarbonate.The aqueous layer was further extracted with dichloromethane (2×30 mL).The combined organics were dried (Na₂SO₄), filtered and concentrated.The crude material was purified by column chromatography (silica gel,90:9:1 ethyl acetate/methanol/concentrated ammonium hydroxide) andsemi-preparative HPLC to afford(S)-N-(1-azabicyclo[2.2.2]oct-3-yl)-2-(3-bromothiophen-2-yl)benzoxazole-4-carboxamide(39 mg, 10%) as a white solid: ¹H NMR (500 MHz, CDCl₃) δ 9.39 (d, J=7.0Hz, 1H), 8.22 (dd, J=7.5, 1.0 Hz, 1H), 7.73 (dd, J=8.0, 1.0 Hz, 1H),7.57 (d, J=8.0 Hz, 1H), 7.50 (t, J=8.0 Hz, 1H), 7.23 (d, J=5.0 Hz, 1H),4.37-4.30 (m, 1H), 3.57-3.50 (m, 1H), 3.14-3.06 (m, 1H), 3.02-2.83 (m,4H), 2.19-2.15 (m, 1H), 2.13-2.05 (m, 1H), 1.82-1.73 (m, 2H), 1.62-1.54(m, 1H); MS (ESI+) m/z 432 (M+H); HPLC >99% (AUC), t_(R)=12.42 min.

Example 127 Preparation ofN-(9-Methyl-9-azabicyclo[3.3.1]non-3-yl)-2-(3-bromothiophen-2-yl)benzoxazole-4-carboxamide

A mixture of 2-(3-bromothiophen-2-yl)benzoxazole-4-carboxylic acid (188mg, 0.58 mmol), 3-amino-9-methyl-9-azabicyclo[3.3.1]nonanedihydrochloride (159 mg, 0.70 mmol),1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (222 mg,1.16 mmol) and 1-hydroxybenzotriazole (157 mg, 1.16 mmol) in DMF (3 mL)was stirred at room temperature for 10 min, then triethylamine (0.40 mL,2.9 mmol) was added. The resulting reaction mixture was stirred at roomtemperature overnight. The mixture was diluted with dichloromethane (30mL), and then washed with a saturated solution of sodium bicarbonate.The aqueous layer was further extracted with dichloromethane (2×30 mL).The combined organics were dried (Na₂SO₄), filtered and concentrated.The crude material was purified by column chromatography (silica gel,90:9:1 ethyl acetate/methanol/concentrated ammonium hydroxide) andrecrystallized from acetonitrile to affordN-(9-methyl-9-azabicyclo[3.3.1]non-3-yl)-2-(3-bromothiophen-2-yl)benzoxazole-4-carboxamide(199 mg, 75%) as a white solid: ¹H NMR (500 MHz, CDCl₃) δ 9.11 (d, J=6.5Hz, 1H), 8.22 (dd, J=7.5, 1.0 Hz, 1H), 7.70 (d, J=8.0 Hz, 1H), 7.58 (d,J=5.5 Hz, 1H), 7.48 (t, J=8.0 Hz, 1H), 7.24 (d, J=5.5 Hz, 1H), 4.68-4.59(m, 1H), 3.22-3.13 (m, 2H), 2.70-2.55 (m, 5H), 2.13-1.98 (m, 3H),1.63-1.49 (m, 3H), 1.26-1.12 (m, 2H); MS (ESI+) m/z 460 (M+H); HPLC >99%(AUC), t_(R)=13.09 min.

Example 128 Preparation of(S)-N-(1-Azabicyclo[2.2.2]oct-3-yl)-6-chloro-2-(3-chlorothiophen-2-yl)benzoxazole-4-carboxamide

Step A: To a suspension of 3-chlorothiophene-2-carboxylic acid (218 mg,1.34 mmol) in dichloromethane (8 mL) was added oxalyl chloride (0.23 mL,2.68 mmol) dropwise, followed by 2 drops of DMF. The reaction wasstirred at room temperature for 2 h. The solvent was evaporated and thesolid directly redissolved in dichloromethane (8 mL).2-Amino-5-chloro-3-hydroxybenzoic acid hydrobromide (359 mg, 1.34 mmol)was added to the reaction mixture followed by triethylamine (0.75 mL,5.40 mmol). The reaction mixture was stirred at room temperatureovernight. The reaction was quenched with aqueous 1 N HCl (20 mL) untilthe solution reached pH 1. The solution was stirred for 30 min. Theaqueous layer was extracted with ethyl acetate. The organic layers werewashed with brine and dried over Na₂SO₄, filtered and concentrated to ayellow solid. The product was directly re-dissolved in toluene (10 mL)and the solution was treated with p-toluenesulfonic acid monohydrate(384 mg, 2.02 mmol). The reaction mixture was then heated to reflux for6 h. The reaction was cooled down to room temperature and the solventwas evaporated. The reaction mixture was poured into water and extractedwith ethyl acetate. The organic layer was separated then washed withwater, brine, dried over Na₂SO₄, filtered and concentrated to a yellowsolid. The crude product was purified by column chromatography (silicagel, 9:1 to 2:1 ethyl acetate/methanol) to afford the desired product(135 mg, 32%) as a yellow solid: ¹H NMR (500 MHz, DMSO-d₆) δ 8.05 (d,J=5.0 Hz, 1H), 7.96 (d, J=1.5 Hz, 1H), 7.73-7.67 (m, 1H), 7.34 (d, J=5.5Hz, 1H); MS (ESI+) m/z 314 (M+H).

Step B: A mixture of6-chloro-2-(3-chlorothiophen-2-yl)benzoxazole-4-carboxylic acid fromStep A (67 mg, 0.21 mmol), (S)-3-aminoquinuclidine dihydrochloride (50mg, 0.25 mmol), 1-ethyl-3-(3-dimethylaminopropyl)carbodiimidehydrochloride (80 mg, 0.42 mmol) and 1-hydroxybenzotriazole (57 mg, 0.42mmol) in DMF (2 mL) was stirred at room temperature, then triethylamine(0.15 mL, 1.05 mmol) was added. The resulting reaction mixture wasstirred at room temperature overnight. The mixture was diluted withdichloromethane (30 mL), and then washed with a saturated solution ofsodium bicarbonate. The aqueous layer was further extracted withdichloromethane (2×30 mL). The combined organics were dried (Na₂SO₄),filtered and concentrated. The crude material was purified by columnchromatography (silica gel, 90:9:1 ethyl acetate/methanol/concentratedammonium hydroxide) and recrystallized from acetonitrile to afford(S)-N-(1-azabicyclo[2.2.2]oct-3-yl)-6-chloro-2-(3-chlorothiophen-2-yl)benzoxazole-4-carboxamide(32 mg, 36%) as a white solid: ¹H NMR (500 MHz, CDCl₃) δ 9.32 (d, J=7.0Hz, 1H), 8.19 (d, J=2.0 Hz, 1H), 7.72 (d, J=2.0 Hz, 1H), 7.61 (d, J=5.0Hz, 1H), 7.16 (d, J=5.0 Hz, 1H), 4.34-4.28 (m, 1H), 3.55-3.48 (m, 2H),3.11-3.05 (m, 1H), 3.02-2.88 (m, 3H), 2.83-2.76 (m, 1H), 2.16-2.12 (m,1H), 2.09-2.01 (m, 1H), 1.81-1.75 (m, 1H), 1.62-1.55 (m, 1H); MS (ESI+)m/z 422 (M+H); HPLC >99% (AUC), t_(R)=12.85 min.

Example 129 Preparation ofN-(9-Methyl-9-azabicyclo[3.3.1]non-3-yl)-6-chloro-2-(3-chlorothiophen-2-yl)benzoxazole-4-carboxamide

A mixture of 6-chloro-2-(3-chlorothiophen-2-yl)benzoxazole-4-carboxylicacid (67 mg, 0.21 mmol), 3-amino-9-methyl-9-azabicyclo[3.3.1]nonanedihydrochloride (57 mg, 0.25 mmol),1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (80 mg, 0.42mmol) and 1-hydroxybenzotriazole (57 mg, 0.42 mmol) in DMF (5 mL) wasstirred at room temperature, then triethylamine (0.15 mL, 1.05 mmol) wasadded. The resulting reaction mixture was stirred at room temperatureovernight. The mixture was diluted with dichloromethane (30 mL), andthen washed with a saturated solution of sodium bicarbonate. The aqueouslayer was further extracted with dichloromethane (2×30 mL). The combinedorganics were dried (Na₂SO₄), filtered and concentrated. The crudematerial was purified by column chromatography (silica gel, 90:9:1 ethylacetate/methanol/concentrated ammonium hydroxide) and recrystallizedfrom acetonitrile to affordN-(9-methyl-9-azabicyclo[3.3.1]non-3-yl)-6-chloro-2-(3-chlorothiophen-2-yl)benzoxazole-4-carboxamide(35 mg, 37%) as a white solid: ¹H NMR (500 MHz, CDCl₃) δ 9.01 (d, J=6.0Hz, 1H), 8.20 (d, J=2.0 Hz, 1H), 7.70 (d, J=1.5 Hz, 1H), 7.61 (d, J=5.5Hz, 1H), 7.17 (d, J=5.0 Hz, 1H), 4.63-4.53 (m, 1H), 3.24-3.13 (m, 2H),2.70-2.55 (m, 5H), 2.12-2.00 (m, 3H), 1.64-1.48 (m, 3H), 1.28-1.12 (m,2H); MS (ESI+) m/z 450 (M+H); HPLC >99% (AUC), t_(R)=13.32 min.

Example 130 Preparation of(S)-N-(1-Azabicyclo[2.2.2]oct-3-yl)-2-(5-methylthiophen-2-yl)benzoxazole-4-carboxamide

Step A: To an ice-cold suspension of 5-methyl-2-thiophenecaboxylic acid(304 mg, 2.14 mmol) in dichloromethane (10 mL) was added oxalyl chloride(0.18 mL, 2.14 mmol) dropwise. Then the ice-water bath was removed andthe mixture was stirred for 1 h. To the above solution was added2-amino-3-hydroxybenzoic acid hydrobromide (0.50 g, 2.14 mmol) followedby triethylamine (1.20 mL, 8.56 mmol). The resulting reaction mixturewas stirred at room temperature overnight. The reaction was quenchedwith water (50 mL). The reaction mixture was extracted withdichloromethane. The aqueous layer was extracted with dichloromethane(2×50 mL). The combined organic layers were dried over Na₂SO₄, filteredand concentrated to afford a yellow solid. The crude was dissolved intoluene (5 mL) and the solution was treated with p-toluenesulfonic acidmonohydrate (464 mg, 2.44 mmol). The reaction mixture was then heated at95° C. under nitrogen for 5 h. The reaction was cooled down to roomtemperature, poured into water and extracted with dichloromethane. Theorganic layer was separated, washed with water, brine, dried overNa₂SO₄, filtered and concentrated to a yellow solid. The crude materialwas purified by recrystallization from methanol to afford the desiredproduct (111 mg, 26%) as an off-white solid: ¹H NMR (500 MHz, DMSO-d₆) δ7.83-7.80 (m, 1H), 7.75-7.70 (m, 2H), 7.58-7.55 (m, 1H), 7.37-7.32 (m,1H), MS (ESI+) m/z 260 (M+H).

Step B: A mixture of 2-(5-methylthiophen-2-yl)benzoxazole-4-carboxylicacid (106 mg, 0.41 mmol), 1-ethyl-3-(3-dimethylaminopropyl)carbodiimidehydrochloride (156 mg, 0.82 mmol), 1-hydroxybenzotriazole (110 mg, 0.82mmol) and (S)-(−)-3-aminoquinuclidine dihydrochloride (101 mg, 0.51mmol) in DMF (3 mL) was stirred at room temperature for 10 min, thentriethylamine (0.23 mL, 1.64 mmol) was added. The resulting reactionmixture was stirred at room temperature overnight. The mixture wasdiluted with dichloromethane and then washed with a saturated solutionof sodium bicarbonate. The aqueous layer was further extracted withdichloromethane (2×50 mL). The combined organic layers were washed withbrine (2×50 mL), dried (Na₂SO₄), filtered and concentrated. The crudematerial was purified by column chromatography (silica gel, 90:9:1dichloromethane/methanol/concentrated ammonium hydroxide) andrecrystallization from acetonitrile to afford(S)-N-(1-azabicyclo[2.2.2]oct-3-yl)-2-(5-methylthiophen-2-yl)benzoxazole-4-carboxamide(19 mg, 13%) as a light yellow solid: ¹H NMR (500 MHz, CDCl₃) δ 9.55 (d,J=7.4 Hz, 1H), 8.15 (dd, J=7.8, 0.9 Hz, 1H), 7.74 (d, J=3.7 Hz, 1H),7.65 (dd, J=7.2, 1.0 Hz, 1H), 7.42 (t, J=7.9 Hz, 1H), 6.89 (dd, J=3.7,1.0 Hz, 1H), 4.35-4.30 (m, 1H), 3.55-3.48 (m, 1H), 3.16-3.07 (m, 2H),2.96-2.91 (m, 2H), 2.86-2.82 (m, 1H), 2.60 (s, 3H), 2.18-2.12 (m, 2H),1.80-1.75 (m, 2H), 1.71-1.65 (m, 1H); MS (ESI+) m/z 368 (M+H); HPLC98.0% (AUC), t_(R)=12.40 min.

Example 131 Preparation of(S)-N-(1-Azabicyclo[2.2.2]oct-3-yl)-2-(5-chloro-thiophen-2-yl)benzoxazole-4-carboxamide

Step A: To an ice-cold suspension of 5-chlorothiophene-2-caboxylic acid(347 mg, 2.14 mmol) in dichloromethane (15 mL) was added oxalyl chloride(0.18 mL, 2.14 mmol) dropwise. Then the ice-water bath was removed andthe mixture was stirred for 1 h. To the above solution was added2-amino-3-hydroxybenzoic acid hydrobromide (0.50 g, 2.14 mmol) followedby the addition of triethylamine (1.19 mL, 8.56 mmol). The resultingreaction mixture was stirred at room temperature overnight. The reactionwas quenched with water (50 mL). The reaction mixture was extracted withdichloromethane. The aqueous layer was extracted with dichloromethane(2×50 mL). The combined organic layers were dried over Na₂SO₄, filteredand concentrated to afford a yellow solid. The crude was dissolved intoluene (10 mL) and the solution was treated with p-toluenesulfonic acidmonohydrate (258 mg, 1.36 mmol). The reaction mixture was then heated at95° C. under nitrogen for 6 h. The reaction was cooled down to roomtemperature, poured into water and extracted with dichloromethane. Theorganic layer was separated, washed with water, brine, dried overNa₂SO₄, filtered and concentrated to a yellow solid. The crude materialwas purified by column chromatography (silica gel, 90:9:1 ethylacetate/methanol/concentrated ammonium hydroxide) to afford the desiredproduct (225 mg, 38%) as an off-white solid: ¹H NMR (500 MHz, DMSO-d₆) δ8.01 (dd, J=8.2, 0.9 Hz, 1H), 7.93-7.90 (m, 2H), 7.52 (t, J=4.0 Hz, 1H),7.39 (d, J=4.0 Hz, 1H); MS (ESI+) m/z 280 (M+H).

Step B: A mixture of 2-(5-chlorothiophen-2-yl)benzoxazole-4-carboxylicacid (110 mg, 0.39 mmol), 1-ethyl-3-(3-dimethylaminopropyl)carbodiimidehydrochloride (149 mg, 0.78 mmol), 1-hydroxybenzotriazole (106 mg, 0.78mmol) and (S)-(−)-3-aminoquinuclidine dihydrochloride (135 mg, 0.49mmol) in DMF (3 mL) was stirred at room temperature for 10 min, thentriethylamine (0.22 mL, 1.4 mmol) was added. The resulting reactionmixture was stirred at room temperature overnight. The mixture wasdiluted with dichloromethane and then washed with a saturated solutionof sodium bicarbonate. The aqueous layer was further extracted withdichloromethane (2×50 mL). The combined organic layers were washed withbrine (50 mL), dried (Na₂SO₄), filtered and concentrated. The crudematerial was purified by column chromatography (silica gel, 90:9:1dichloromethane/methanol/concentrated ammonium hydroxide) to afford(S)-N-(1-azabicyclo[2.2.2]oct-3-yl)-2-(5-chloro-thiophen-2-yl)benzoxazole-4-carboxamide(22 mg, 17%) as a white solid: ¹H NMR (500 MHz, CDCl₃) δ 9.41 (d, J=7.3Hz, 1H), 8.17 (dd, J=7.8, 1.0 Hz, 1H), 7.73 (d, J=4.1 Hz, 1H), 7.69 (dd,J=8.2, 1.0 Hz, 1H), 7.48 (t, J=8.0 Hz, 1H), 7.06 (d, J=4.0 Hz, 1H),4.50-4.45 (m, 1H), 3.65-3.60 (m, 1H), 3.30-3.20 (m, 2H), 3.15-3.05 (m,2H), 3.02-2.95 (m, 1H), 2.30-2.55 (m, 2H), 1.95-1.78 (m, 3H); MS (ESI+)m/z 388 (M+H); HPLC >99% (AUC), t_(R)=12.59 min.

Example 132 Preparation ofN-(9-Methyl-9-azabicyclo[3.3.1]non-3-yl)-2-(5-chlorothiophene-2-yl)benzoxazole-4-carboxamide

A mixture of 2-(5-chlorothiophen-2-yl)benzoxazole-4-carboxylic acid (110mg, 0.39 mmol), 1-ethyl-3-(3-dimethylaminopropyl)carbodiimidehydrochloride (149 mg, 0.78 mmol), 1-hydroxybenzotriazole (106 mg, 0.78mmol) and 3-amino-9-methyl-9-azabicyclo[3.3.1]nonane dihydrochloride(111 mg, 0.48 mmol) in DMF (5 mL) was stirred at room temperature for 10min, then triethylamine (0.22 mL, 1.56 mmol) was added. The resultingreaction mixture was stirred at room temperature overnight. The mixturewas diluted with dichloromethane and then washed with a saturatedsolution of sodium bicarbonate. The aqueous layer was further extractedwith dichloromethane (2×50 mL). The combined organic layers were washedwith water (2×50 mL), brine (2×50 mL), dried (Na₂SO₄), filtered andconcentrated. The crude material was purified by column chromatography(silica gel, 90:9:1 dichloromethane/methanol/concentrated ammoniumhydroxide) and recrystallization from acetonitrile to affordN-(9-methyl-9-azabicyclo[3.3.1]non-3-yl)-2-(5-chlorothiophene-2-yl)benzoxazole-4-carboxamide(19 mg, 12%) as a light brown solid: ¹H NMR (500 MHz, CDCl₃) δ 8.85 (d,J=6.3 Hz, 1H), 8.20 (dd, J=7.8, 1.0 Hz, 1H), 7.73 (d, J=4.0 Hz, 1H),7.65 (dd, J=8.1, 1.0 Hz, 1H), 7.45 (t, J=7.9 Hz, 1H), 7.06 (d, J=4.1 Hz,1H), 4.60-4.54 (m, 1H), 3.20-3.10 (m, 2H), 2.67-2.58 (m, 2H), 2.56 (s,3H), 2.20-2.00 (m, 3H), 1.60-1.45 (m, 3H), 1.25-1.15 (m, 2H); MS (ESI+)m/z 416 (M+H); HPLC >99% (AUC), t_(R)=13.02 min.

Example 133 Preparation of(S)-N-(1-Azabicyclo[2.2.2]oct-3-yl)-2-(5-bromothiophene-2-yl)benzoxazole-4-carboxamide

Step A: To an ice-cold suspension of 5-bromothiophene-2-caboxylic acid(2.07 g, 10.0 mmol) in dichloromethane (20 mL) was added oxalyl chloride(0.18 mL, 2.14 mmol) dropwise. Then the ice-water bath was removed andthe mixture was stirred for 1 h. To the above solution was added2-amino-3-hydroxybenzoic acid hydrobromide (2.34 g, 10.0 mmol) followedby the addition of triethylamine (5.57 mL, 40.0 mmol). The resultingreaction mixture was stirred at room temperature overnight. The reactionwas quenched with 1 N HCl (50 mL), and the reaction mixture wasextracted with dichloromethane. The aqueous layer was extracted withdichloromethane (2×100 mL). The combined organic layers were dried overNa₂SO₄, filtered and concentrated to afford a yellow solid. The crudewas dissolved in toluene (15 mL) and the solution was treated withp-toluenesulfonic acid monohydrate (0.87 g, 4.59 mmol). The reactionmixture was then heated to reflux under nitrogen for 6 h. The reactionwas cooled down to room temperature, poured into water and extractedwith dichloromethane. The organic layer was separated, washed withwater, brine, dried over Na₂SO₄, filtered and concentrated to a yellowsolid. The crude material was purified by recrystallization fromdichloromethane and ethyl acetate to afford the desired product (356 mg,25%) as an off-white solid: ¹H NMR (500 MHz, DMSO-d₆) δ 13.17 (s, 1H),8.01 (dd, J=8.2, 1.0 Hz, 1H), 8.91 (dd, J=7.8, 1.0 Hz, 1H), 7.86 (d,J=4.3 Hz, 1H), 7.52 (t, J=8.2 Hz, 1H), 7.48 (d, J=4.0 Hz, 1H); MS (ESI+)m/z 324 (M+H).

Step B: A mixture of 2-(5-bromo-2-thiophene)benzoxazole-4-carboxylicacid (64 mg, 0.20 mmol), 1-ethyl-3-(3-dimethylaminopropyl)carbodiimidehydrochloride (76 mg, 0.40 mmol), 1-hydroxybenzotriazole (54 mg, 0.40mmol) and (S)-(−)-3-aminoquinuclidine dihydrochloride (50 mg, 0.25 mmol)in DMF (4 mL) was stirred 10 min at room temperature, then triethylamine(0.10 mL, 0.80 mmol) was added. The resulting reaction mixture wasstirred at room temperature overnight. The mixture was diluted withdichloromethane and then washed with a saturated solution of sodiumbicarbonate. The aqueous layer was further extracted withdichloromethane (2×50 mL). The combined organic layers were washed withbrine (2×50 mL), dried (Na₂SO₄), filtered and concentrated. The crudematerial was purified by column chromatography (silica gel, 90:9:1dichloromethane/methanol/concentrated ammonium hydroxide) to afford(S)-N-(1-azabicyclo[2.2.2]oct-3-yl)-2-(5-bromothiophene-2-yl)benzoxazole-4-carboxamide(76 mg, 88%) as a light yellow solid: ¹H NMR (500 MHz, CDCl₃) δ 9.38 (d,J=7.4 Hz, 1H), 8.19 (dd, J=7.8, 1.0 Hz, 1H), 7.69-7.65 (m, 2H), 7.48 (t,J=7.9 Hz, 1H), 7.19 (d, J=4.0 Hz, 1H), 4.35-4.25 (m, 1H), 3.55-3.48 (m,1H), 3.15-3.03 (m, 2H), 2.95-2.90 (m, 2H), 2.85-2.76 (m, 1H), 2.15-2.05(m, 2H), 1.80-1.62 (m, 3H); MS (ESI+) m/z 432 (M+H); HPLC >99% (AUC),t_(R)=12.79 min.

Example 134 Preparation ofN-(9-Methyl-9-azabicyclo[3.3.1]non-3-yl)-2-(5-bromothiophene-2-yl)benzoxazole-4-carboxamide

A mixture of 2-(5-bromothiophene)benzoxazole-4-carboxylic acid (64 mg,0.20 mmol), 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride(76 mg, 0.40 mmol), 1-hydroxybenzotriazole (54 mg, 0.40 mmol) and3-amino-9-methyl-9-azabicyclo[3.3.1]nonane dihydrochloride (69 mg, 0.25mmol) in DMF (4 mL) was stirred at room temperature for 10 min, thentriethylamine (0.11 mL, 0.80 mmol) was added. The resulting reactionmixture was stirred at room temperature overnight. The mixture wasdiluted with dichloromethane and then washed with a saturated solutionof sodium bicarbonate. The aqueous layer was further extracted withethyl acetate (2×100 mL). The combined organic layers were washed withwater (2×100 mL), brine (2×100 mL), dried (Na₂SO₄), filtered andconcentrated. The crude material was purified by column chromatography(silica gel, 90:9:1 dichloromethane/methanol/concentrated ammoniumhydroxide) and recrystallizations to affordN-(9-methyl-9-azabicyclo[3.3.1]non-3-yl)-2-(5-bromothiophene-2-yl)benzoxazole-4-carboxamide(39 mg, 42%) as a light yellow solid: ¹H NMR (500 MHz, CDCl₃) δ 8.84 (d,J=6.2 Hz, 1H), 8.20 (dd, J=7.8, 1.0 Hz, 1H), 7.69 (d, J=3.9 Hz, 1H),7.65 (dd, J=8.1, 1.0 Hz, 1H), 7.45 (t, J=7.9 Hz, 1H), 7.20 (d, J=4.1 Hz,1H), 4.60-4.54 (m, 1H), 3.20-3.10 (m, 2H), 2.67-2.60 (m, 2H), 2.56 (s,3H), 2.20-2.00 (m, 3H), 1.62-1.47 (m, 3H), 1.26-1.17 (m, 2H); MS (ESI+)m/z 460 (M+H); HPLC >99% (AUC), t_(R)=13.02 min.

Example 135 Preparation of(S)-N-(1-Azabicyclo[2.2.2]oct-3-yl)-6-chloro-2-(5-methylthiophen-2-yl)benzoxazole-4-carboxamide

Step A: To an ice-cold suspension of 5-methyl-2-thiophenecarboxyl acid(400 mg, 2.14 mmol) in dichloromethane (20 mL) was added oxalyl chloride(0.21 mL, 2.14 mmol) dropwise followed by a few drops of DMF. Then theice-water bath was removed and the reaction mixture was stirred for 1 h.To the above solution was added 2-amino-3-hydroxybenzoic acidhydrobromide (0.50 g, 2.14 mmol) followed by triethylamine (1.19 mL,8.56 mmol). The resulting reaction mixture was stirred at roomtemperature overnight. The reaction was quenched with 1 N HCl (20 mL).The reaction mixture was extracted with dichloromethane. The aqueouslayer was extracted with dichloromethane (2×50 mL). The combined organiclayers were dried over Na₂SO₄, filtered and concentrated to afford ayellow solid. The crude was dissolved in toluene (5 mL) and the solutionwas treated with p-toluenesulfonic acid monohydrate (619 mg, 3.25 mmol).The reaction mixture was then heated to reflux under nitrogen for 3 h.The reaction was cooled down to room temperature, poured into water andextracted with dichloromethane. The organic layer was separated, washedwith water, brine, dried over Na₂SO₄, filtered and concentrated to ayellow solid. The crude material was recrystallized from methanol toafford the desired product (198 mg, 48%) as an off-white solid (78 mg,12%): ¹H NMR (500 MHz, DMSO-d₆) δ 8.20 (d, J=2.1 Hz, 1H), 7.84 (d, J=3.7Hz, 1H), 7.83 (d, J=2.2 Hz, 1H), 7.06 (dd, J=3.7, 1.1 Hz, 1H), 3.17 (s,3H), MS (ESI+) m/z 293 (M+H).

Step B: A mixture of6-chloro-2-(5-methylthiophen-2-yl)benzoxazole-4-carboxylic acid (41 mg,0.14 mmol), 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride(53 mg, 0.28 mmol), 1-hydroxybenzotriazole (38 mg, 0.28 mmol) and(S)-(−)-3-aminoquinuclidine dihydrochloride (35 mg, 0.17 mmol) in DMF (2mL) was stirred at room temperature for 10 min, then triethylamine (0.08mL, 0.56 mmol) was added. The resulting reaction mixture was stirred atroom temperature for 4 h. The mixture was diluted with dichloromethaneand then washed with a saturated solution of sodium bicarbonate. Theaqueous layer was further extracted with dichloromethane (2×50 mL). Thecombined organic layers were washed with brine (2×25 mL), dried(Na₂SO₄), filtered and concentrated. The crude material was purified bycolumn chromatography (silica gel, 90:9:1dichloromethane/methanol/concentrated ammonium hydroxide) andrecrystallization from acetonitrile to afford(S)-N-(1-azabicyclo[2.2.2]oct-3-yl)-6-chloro-2-(5-methylthiophen-2-yl)benzoxazole-4-carboxamide(30 mg, 55%) as a white solid: ¹H NMR (500 MHz, CDCl₃) δ 9.43 (d, J=7.4Hz, 1H), 8.12 (d, J=1.9 Hz, 1H), 7.74 (d, J=3.7 Hz, 1H), 7.64 (d, J=1.9Hz, 1H), 6.90 (dd, J=3.7, 0.9 Hz, 1H), 4.33-4.29 (m, 1H), 3.54-3.47 (m,1H), 3.15-3.03 (m, 2H), 2.95-2.90 (m, 2H), 2.85-2.79 (m, 1H), 2.61 (s,3H), 2.15-2.05 (m, 2H), 1.86-1.76 (m, 2H), 1.75-1.65 (m, 1H); MS (ESI+)m/z 402 (M+H); HPLC >99% (AUC), t_(R)=12.99 min.

Example 136 Preparation ofN-(9-Methyl-9-azabicyclo[3.3.1]non-3-yl)-6-chloro-2-(5-methylthiophen-2-yl)benzoxazole-4-carboxamide

A mixture of 6-cholro-2-(5-methylythiophen-2-yl)benzoxazole-4-carboxylicacid (31 mg, 0.11 mmol), 1-ethyl-3-(3-dimethylaminopropyl)carbodiimidehydrochloride (41 mg, 0.21 mmol), 1-hydroxybenzotriazole (29 mg, 0.21mmol) and 3-amino-9-methyl-9-azabicyclo[3.3.1]nonane dihydrochloride (30mg, 0.13 mmol) in DMF (2 mL) was stirred at room temperature for 10 min,then triethylamine (0.059 mL, 0.42 mmol) was added. The resultingreaction mixture was stirred at room temperature for 7 h. The mixturewas diluted with dichloromethane and then washed with a saturatedsolution of sodium bicarbonate. The aqueous layer was further extractedwith dichloromethane (2×50 mL). The combined organic layers were washedwith water (2×25 mL), brine (2×25 mL), dried (Na₂SO₄), filtered andconcentrated. The crude material was purified by column chromatography(silica gel, 90:9:1 ethyl acetate/methanol/concentrated ammoniumhydroxide) and recrystallization from acetonitrile to affordN-(9-methyl-9-azabicyclo[3.3.1]non-3-yl)-6-chloro-2-(5-methylthiophen-2-yl)benzoxazole-4-carboxamide(21 mg, 47%) as an off-white solid: ¹H NMR (500 MHz, CDCl₃) δ 8.90 (brs, 1H), 8.15 (d, J=2.0 Hz, 1H), 7.75 (d, J=3.7 Hz, 1H), 7.62 (d, J=2.0Hz, 1H), 6.90 (dd, J=3.7, 1.0 Hz, 1H), 4.60-4.52 (m, 1H), 4.20-4.10 (m,2H), 2.70-2.65 (m, 1H), 2.61 (s, 3H), 2.58 (s, 3H), 2.40-2.00 (m, 3H),1.65-1.50 (m, 4H), 1.35-1.15 (m, 2H); MS (ESI+) m/z 430 (M+H); HPLC >99%(AUC), t_(R)=13.48 min.

Example 137 Preparation of(S)-N-(1-Azabicyclo[2.2.2]oct-3-yl)-2-(5,6-dihydro-4H-cyclopenta[b]thiophen-2-yl)benzoxazole-4-carboxamide

Step A: Oxalyl chloride (0.11 mL, 1.31 mmol) was added to a suspensionof 5,6-dihydro-4H-cyclopent[b]thiophene-2-carboxylic acid (200 mg, 1.19mmol) in methylene chloride (2 mL) at room temperature and the mixturewas stirred under nitrogen for 2 h. 3-Hydroxyanthranilic acidhydrobromide (278 mg, 1.19 mmol) was added, followed by triethylamine(0.83 mL, 5.95 mmol) and methylene chloride (3 mL). The resultingmixture was stirred under nitrogen overnight, and then quenched with 1 NHCl. The organic layer was separated and the aqueous layer was extractedwith methylene chloride. The combined organic layers were washed withbrine, dried over sodium sulfate, filtered and concentrated in vacuo togive the crude product (340 mg, 94%) as a light yellow solid: ¹H NMR(500 MHz, CDCl₃) δ 11.75 (br s, 1H), 10.28 (br s, 1H), 7.73 (dd, J=8.0,1.5 Hz, 1H), 7.57 (s, 1H), 7.33 (dd, J=8.0, 1.5 Hz, 1H), 7.18 (t, J=8.0Hz, 1H), 2.98 (t, J=7.5 Hz, 2H), 2.81 (t, J=7.5 Hz, 2H), 2.53-2.47 (m,2H); MS (ESI+) m/z 304 (M+H).

Step B: A mixture of the amide from Step A (340 mg, 1.12 mmol),p-toluenesulfonic acid monohydrate (213 mg, 1.12 mmol) and toluene (10mL) was heated at 100° C. under nitrogen overnight. The reaction mixturewas cooled to room temperature, quenched with 1 N HCl, extracted withmethylene chloride, washed with brine, dried over sodium sulfate,filtered and concentrated. The crude material was purified by columnchromatography (silica gel, 70:30 ethyl acetate/methanol) to afford theacid (180 mg, 56%) as a light yellow solid: ¹H NMR (500 MHz, DMSO-d₆) δ12.95 (br s, 1H), 7.96 (dd, J=8.0, 1.0 Hz, 1H), 7.88 (dd, J=8.0, 1.0 Hz,1H), 7.77 (s, 1H), 7.46 (t, J=8.0 Hz, 1H), 2.98 (t, J=7.5 Hz, 2H), 2.78(t, J=7.5 Hz, 2H), 2.48-2.42 (m, 2H); MS (ESI+) m/z 286 (M+H).

Step C: A mixture of the carboxylic acid from Step B (90 mg, 0.32 mmol),(S)-3-aminoquinuclidine dihydrochloride (76 mg, 0.38 mmol),1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (122 mg,0.64 mmol) and 1-hydroxybenzotriazole (86 mg, 0.64 mmol) in DMF (5 mL)was stirred under nitrogen at room temperature for 10 min, and thentriethylamine (0.27 mL, 1.92 mmol) was added. The resulting reactionmixture was stirred at room temperature overnight, and then was quenchedwith a saturated solution of sodium bicarbonate, extracted withmethylene chloride. The combined organic layers were dried (Na₂SO₄),filtered and concentrated. The crude material was purified by columnchromatography (silica gel, 90:9:1 ethyl acetate/methanol/concentratedammonium hydroxide) to afford(S)-N-(1-azabicyclo[2.2.2]oct-3-yl)-2-(5,6-dihydro-4H-cyclopenta[b]thiophen-2-yl)benzoxazole-4-carboxamide(82 mg, 66%) as a light yellow solid: ¹H NMR (500 MHz, CDCl₃) δ 9.56 (d,J=7.5 Hz, 1H), 8.14 (dd, J=8.0, 1.0 Hz, 1H), 7.63 (s, 1H), 7.62 (dd,J=8.0, 1.0 Hz, 1H), 7.40 (t, J=8.0 Hz, 1H), 4.32-4.28 (m, 1H), 3.47(ddd, J=14.0, 9.5, 2.0 Hz, 1H), 3.12-2.98 (m, 4H), 2.92-2.77 (m, 5H),2.57-2.50 (m, 2H), 2.12-2.07 (m, 2H), 1.76-1.58 (m, 3H); MS (ESI+) m/z394 (M+H); HPLC >99% (AUC), t_(R)=13.28 min.

Example 138 Preparation ofN-(9-Methyl-9-azabicyclo[3.3.1]non-3-yl)-2-(5,6-dihydro-4H-cyclopenta[b]thiophen-2-yl)benzoxazole-4-carboxamide

A mixture of2-(5,6-dihydro-4H-cyclopenta[b]thiophen-2-yl)benzo[d]oxazole-4-carboxylicacid (90 mg, 0.32 mmol), 3-amino-9-methyl-9-azabicyclo[3.3.1]nonanedihydrochloride (86 mg, 0.38 mmol),1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (122 mg,0.64 mmol) and 1-hydroxybenzotriazole (86 mg, 0.64 mmol) in DMF (5 mL)was stirred under nitrogen at room temperature for 10 min, and thentriethylamine (0.27 mL, 1.92 mmol) was added. The resulting reactionmixture was stirred at room temperature overnight, and then was quenchedwith a saturated solution of sodium bicarbonate, extracted withmethylene chloride. The combined organic layers were washed with brine,dried (Na₂SO₄), filtered and concentrated. The crude material waspurified by column chromatography (silica gel, 90:9:1 ethylacetate/methanol/concentrated ammonium hydroxide) and semi-preparativeHPLC to affordN-(9-methyl-9-azabicyclo[3.3.1]non-3-yl)-2-(5,6-dihydro-4H-cyclopenta[b]thiophen-2-yl)benzoxazole-4-carboxamide(55 mg, 41%) as a light yellow solid: ¹H NMR (500 MHz, CDCl₃) δ 9.01 (d,J=7.5 Hz, 1H), 8.16 (dd, J=8.0, 1.0 Hz, 1H), 7.65 (s, 1H), 7.61 (dd,J=8.0, 1.0 Hz, 1H), 7.39 (t, J=8.0 Hz, 1H), 4.60-4.50 (m, 1H), 3.10 (d,J=10.0 Hz, 2H), 3.03-3.00 (m, 2H), 2.86-2.82 (m, 2H), 2.65-2.52 (m, 4H),2.54 (s, 3H), 2.18-1.96 (m, 3H), 1.62-1.46 (m, 3H), 1.25-1.18 (m, 2H);MS (ESI+) m/z 422 (M+H); HPLC >99% (AUC), t_(R)=13.28 min.

Example 139 Preparation of(S)-N-(1-Azabicyclo[2.2.2]oct-3-yl)-2-(3,5-dimethylisoxazole-4-yl)benzoxazole-4-carboxamide

Step A: To a suspension of 2-amino-3-hydroxybenzoic acid hydrobromide(500 mg, 2.14 mmol) in dichloromethane (15 mL) was added triethyamine(1.19 mL, 8.56 mmol) followed by 3,5-dimethylisoxazole-4-carbonylchloride (341 mg, 2.14 mmol) at room temperature. The resulting reactionmixture was stirred at room temperature overnight. The reaction wasquenched with aqueous 2 N HCl (50 mL). The reaction mixture wasextracted with dichloromethane. The combined organic layers were driedover Na₂SO₄, filtered and concentrated to a brown solid. The crude wasdissolved in toluene (10 mL) and the solution was treated withp-toluenesulfonic acid monohydrate (0.581 g, 3.06 mmol). The resultingreaction mixture was then heated to reflux under nitrogen for 4 h. Thereaction was cooled down to room temperature, poured into water andextracted with ethyl acetate (400 mL). The organic layer was separatedthen washed with water, brine, dried over Na₂SO₄, filtered andconcentrated to an off-white solid. The crude product was purified byrecrystallization from ethyl acetate to afford the desired product (271mg, 49%) as an off-white solid: ¹H NMR (500 MHz, DMSO-d₆) δ 13.04 (br s,1H), 8.03 (dd, J=8.1, 0.8 Hz, 1H), 8.16 (dd, J=7.8, 0.9 Hz, 1H), 2.87(s, 3H), 2.61 (s, 3H); MS (ESI+) m/z 259 (M+H).

Step B: A mixture of2-(3,5-dimethylisoxazol-4-yl)benzoxazole-4-carboxylic acid (136 mg, 0.53mmol), 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (201mg, 1.05 mmol), 1-hydroxybenzotriazole (142 mg, 1.05 mmol) and(S)-(−)-3-aminoquinuclidine dihydrochloride (131 mg, 0.66 mmol) in DMF(5 mL) was stirred at room temperature for 10 min, then triethylamine(0.56 mL, 4.0 mmol) was added. The resulting reaction mixture wasstirred at room temperature overnight. The mixture was diluted withdichloromethane (100 mL), and then washed with a saturated solution ofsodium bicarbonate. The aqueous layer was further extracted withdichloromethane (2×50 mL). The combined organics were washed with water(5×25 mL), brine (25 mL), dried (Na₂SO₄), filtered and concentrated. Thecrude material was purified by column chromatography (silica gel, 90:9:1methylene chloride/methanol/concentrated ammonium hydroxide) andrecrystallization from acetonitrile to afford(S)-N-(1-azabicyclo[2.2.2]oct-3-yl)-2-(3,5-dimethylisoxazole-4-yl)benzoxazole-4-carboxamide(91 mg, 47%) as a white solid: ¹H NMR (500 MHz, CDCl₃) δ 9.09 (d, J=6.5Hz, 1H), 8.22 (dd, J=7.8, 1.0 Hz, 1H), 7.72 (dd, J=8.1, 1.0 Hz, 1H),7.49 (t, J=8.0 Hz, 1H), 4.33-4.29 (m, 1H), 3.58-3.53 (m, 1H), 3.00-2.90(m, 3H), 2.89 (s, 3H), 2.76-2.71 (m, 1H), 2.69 (s, 3H), 2.15-2.10 (m,1H), 1.97-1.85 (m, 2H), 1.80-1.70 (m, 2H), 1.61-1.50 (m, 1H); MS (ESI+)m/z 367 (M+H); HPLC >99% (AUC), t_(R)=11.69 min.

Example 140 Preparation ofN-(9-Methyl-9-azabicyclo[3.3.1]non-3-yl)-2-(3,5-dimethylisoxazole-4-yl)benzoxazole-4-carboxamide

A mixture of 2-(3,5-dimethylisoxazol-4-yl)benzoxazole-4-carboxylic acid(136 mg, 0.53 mmol), 1-ethyl-3-(3-dimethylaminopropyl)carbodiimidehydrochloride (201 mg, 1.05 mmol), 1-hydroxybenzotriazole (142 mg, 1.05mmol) and 3-amino-9-methyl-9-azabicyclo[3.3.1]nonane dihydrochloride(150 mg, 0.66 mmol) in DMF (5 mL) was stirred at room temperature for 10min, then triethylamine (0.29 mL, 2.11 mmol) was added. The resultingreaction mixture was stirred at room temperature overnight. The mixturewas diluted with ethyl acetate and then washed with a saturated solutionof sodium bicarbonate. The aqueous layer was further extracted withethyl acetate (2×100 mL). The combined organic layers were washed withbrine (2×100 mL), dried (Na₂SO₄), filtered and concentrated. The crudematerial was purified by column chromatography (silica gel, 90:9:1 ethylacetate/methanol/concentrated ammonium hydroxide) and recrystallizationfrom acetonitrile to affordN-(9-methyl-9-azabicyclo[3.3.1]non-3-yl)-2-(3,5-dimethylisoxazole-4-yl)benzoxazole-4-carboxamide(99 mg, 48%) as a white solid: ¹H NMR (500 MHz, CDCl₃) δ 8.85 (d, J=6.6Hz, 1H), 8.22 (dd, J=7.7, 1.0 Hz, 1H), 7.69 (dd, J=8.0, 0.9 Hz, 1H),7.47 (t, J=7.9 Hz, 1H), 4.66-4.60 (m, 1H), 4.22-4.15 (m, 2H), 2.90 (s,3H), 2.71 (s, 3H), 2.68-2.60 (m, 2H), 2.57 (s, 3H), 2.07-1.96 (m, 3H),1.90-1.61 (m, 3H), 1.15-1.05 (m, 2H); MS (ESI+) m/z 395 (M+H); HPLC >99%(AUC), t_(R)=12.33 min.

Example 141 Preparation of(S)-N-(1-Azabicyclo[2.2.2]oct-3-yl)-2-(4-methylthiazol-5-yl)benzoxazole-4-carboxamideHydrochloride

Step A: To an ice-cold solution of 4-methyl-5-thiozolcarboxylic acid(306 mg, 2.14 mmol) in dichloromethane (20 mL) was added oxalyl chloride(0.21 mL, 2.14 mmol) dropwise. The ice bath was removed and stirring wascontinued for 1 h. 2-Amino-3-hydroxybenzoic acid hydrobromide (500 mg,2.14 mmol) was added, followed by triethylamine (0.90 mL, 6.42 mmol).The resulting reaction mixture was stirred at room temperatureovernight. The reaction was quenched with aqueous 1 N HCl (25 mL) untilthe solution reached pH 1 and stirred for 30 min. The aqueous layer wasextracted with dichloromethane. The organic layers were washed withbrine, dried over Na₂SO₄, filtered and concentrated. The residue wasdirectly re-dissolved in toluene (10 mL) and the solution was treatedwith p-toluenesulfonic acid monohydrate (517 mg, 1.85 mmol). Thereaction mixture was then heated to reflux for 5 h. The reaction wascooled down to room temperature, poured into water and extracted withethyl acetate. The organic layer was separated, washed with water andbrine, dried over Na₂SO₄, filtered and concentrated to a yellow solid.The crude product was purified by re-crystallization from ethyl acetateto afford the desired product (115 mg, 24%) as a yellow solid: ¹H NMR(300 MHz, DMSO-d₆) δ 13.50 (br s, 1H), 9.31 (s, 1H), 8.05 (dd, J=14.0,2.0 Hz, 1H), 7.93 (dd, J=7.8, 1.2 Hz, 1H), 7.22 (t, J=7.5 Hz, 1H), 2.91(s, 3H); MS (ESI+) m/z 261 (M+H).

Step B: A mixture of 2-(4-methylthiazol-5-yl)benzoxazole-4-carboxylicacid (80 mg, 0.31 mmol), 1-ethyl-3-(3-dimethylaminopropyl)carbodiimidehydrochloride (118 mg, 0.62 mmol), 1-hydroxybenzotriazole (84 mg, 0.62mmol) and (S)-(−)-3-aminoquinuclidine dihydrochloride (73 mg, 0.39 mmol)in DMF (5 mL) was stirred at room temperature for 10 min, thentriethylamine (0.18 mL, 4.0 mmol) was added. The resulting reactionmixture was stirred at room temperature overnight. The mixture wasdiluted with ethyl acetate (50 mL), and then washed with a saturatedsolution of sodium bicarbonate. The aqueous layer was further extractedwith ethyl acetate (2×100 mL). The combined organics were washed withwater (2×50 mL) and brine (2×50 mL), dried (Na₂SO₄), filtered andconcentrated. The crude material was purified by column chromatography(silica gel, 90:9:1 dichloromethane/methanol/concentrated ammoniumhydroxide) and recrystallization from acetonitrile to afford the desiredproduct (49 mg, 45%) as a yellow solid: ¹H NMR (500 MHz, CDCl₃) δ 9.28(d, J=7.3 Hz, 1H), 8.90 (s, 1H), 8.22 (dd, J=7.8, 1.0 Hz, 1H), 7.72 (dd,J=8.1, 1.0 Hz, 1H), 7.49 (t, J=8.0 Hz, 1H), 4.40-4.30 (m, 1H), 3.58-3.53(m, 1H), 3.10-3.03 (m, 2H), 3.00 (s, 3H), 2.98-2.94 (m, 2H), 2.90-2.78(m, 1H), 2.20-2.15 (m, 1H), 2.10-2.00 (m, 1H), 1.85-1.76 (m, 2H),1.66-1.63 (m, 1H); MS (ESI+) m/z 369 (M+H).

Step C: To a solution of(S)-N-(1-azabicyclo[2.2.2]oct-3-yl)-2-(4-methylthiazol-5-yl)benzoxazole-4-carboxamide(45 mg, 0.12 mmol) in methanol (2.0 mL) was added a solution of HCl indiethyl ether (1 N, 1.5 mL, 1.5 mmol) at room temperature slowly. Thereaction mixture was diluted with diethyl ether. The resulting solid wasfiltered and washed with diethyl ether to afford(S)-N-(1-azabicyclo[2.2.2]oct-3-yl)-2-(4-methylthiazol-5-yl)benzoxazole-4-carboxamidehydrochloride (40 mg, 74%) as a light yellow solid: ¹H NMR (500 MHz,DMSO-d₆) δ 10.46 (s, 1H), 9.35 (s, 1H), 9.10 (d, J=6.3 Hz, 1H), 8.05(dd, J=8.2, 0.9 Hz, 1H), 7.94 (dd, J=7.7, 0.9 Hz, 1H), 7.58 (t, J=8.0Hz, 1H), 4.44-4.40 (m, 1H), 3.64-3.55 (m, 1H), 3.35-3.15 (m, 5H),2.91(s, 3H), 2.33-2.25 (m, 2H), 2.00-1.95 (m, 3H); MS (ESI+) m/z 369(M+H); HPLC >99% (AUC), t_(R)=12.05 min.

Example 142 Preparation ofN-(9-Methyl-9-azabicyclo[3.3.1]non-3-yl)-2-(4-methylthiazol-5-yl)benzoxazole-4-carboxamideHydrochloride

Step A: A mixture of 2-(4-methylthiazol-5-yl)benzoxazole-4-carboxylicacid (60 mg, 0.23 mmol), 1-ethyl-3-(3-dimethylaminopropyl)carbodiimidehydrochloride (88 mg, 0.46 mmol), 1-hydroxybenzotriazole (62 mg, 0.46mmol) and 3-amino-9-methyl-9-azabicyclo[3.3.1]nonane dihydrochloride (65mg, 0.29 mmol) in DMF (5 mL) was stirred at room temperature for 10 min,then triethylamine (0.29 mL, 2.11 mmol) was added. The resultingreaction mixture was stirred at room temperature overnight. The mixturewas diluted with ethyl acetate and then washed with a saturated solutionof sodium bicarbonate. The aqueous layer was further extracted withethyl acetate (2×100 mL). The combined organic layers were washed withbrine (2×100 mL), dried (Na₂SO₄), filtered and concentrated. The crudematerial was purified by column chromatography (silica gel, 90:9:1dichloromethane/methanol/concentrated ammonium hydroxide) andrecrystallization from acetonitrile to afford the desired product (57mg, 63%) as a light yellow solid: ¹H NMR (300 MHz, CDCl₃) δ 8.92 (br s,1H), 8.90 (s, 1H), 8.22 (dd, J=7.8, 1.0 Hz, 1H), 7.69 (dd, J=8.1, 1.0Hz, 1H), 7.48 (t, J=8.0 Hz, 1H), 4.70-4.57 (m, 1H), 3.25-3.10 (m, 2H),3.10 (s, 3H), 2.75-2.60 (m, 2H), 2.57 (s, 3H), 2.15-1.95 (m, 3H),1.65-1.45 (m, 3H), 1.25-1.10 (m, 2H); MS (ESI+) m/z 397 (M+H).

Step C: To a solutionof(S)-N-(1-azabicyclo[2.2.2]oct-3-yl)-2-(4-methylthiazol-5-yl)benzoxazole-4-carboxamide(57 mg, 0.14 mmol) in methanol (2.0 mL) was added a solution of HCl indiethyl ether (1 N, 0.29 mL, 0.29 mmol) at room temperature slowly. Thereaction mixture was diluted with diethyl ether. The resulting solid wasfiltered and washed with diethyl ether to affordN-(9-methyl-9-azabicyclo[3.3.1]non-3-yl)-2-(4-methylthiazol-5-yl)benzoxazole-4-carboxamidehydrochloride (54 mg, 90%) as an off-white solid; ¹H NMR (500 MHz,DMSO-d₆) δ 10.41 (br s, 0.3H), 9.59 (br s, 0.7H), 9.36 (s, 0.7H), 9.34(s, 0.3H), 8.94 (d, J=7.3 Hz, 0.3H), 8.82 (d, J=7.3 Hz, 0.7H), 8.05-8.02(m, 1H), 7.99-7.93 (m, 1H), 7.60-7.54 (m, 1H), 4.70-4.60 (m, 1H),3.70-3.66 (m, 1.3H), 3.62-3.58 (m, 0.7H), 2.94 (s, 2H), 2.91 (s, 1H),2.88-2.82 (m, 3H), 2.75-2.60 (m, 2H), 2.30-2.20 (m, 1H), 2.18-2.05 (m,2H), 1.82-1.75 (m, 2H), 1.63-1.55 (m, 1H), 1.52-1.45 (m, 2H); MS (ESI+)m/z 397 (M+H); HPLC >99% (AUC), t_(R)=12.28 min.

Example 143 Preparation of(S)-N-(1-Azabicyclo[2.2.2]oct-3-yl)-2-(thiazole-4-yl)benzoxazole-4-carboxamideHydrochloride

Step A: To an ice-cold solution of 1,3-thiozol-4-carboxylic acid (276mg, 2.14 mmol) in dichloromethane (20 mL) was added oxalyl chloride(0.21 mL, 2.14 mmol) dropwise. The ice bath was removed and stirring wascontinued for 1 h. 2-Amino-3-hydroxybenzoic acid hydrobromide (500 mg,2.14 mmol) was added followed by triethylamine (0.90 mL, 6.42 mmol). Theresulting reaction mixture was stirred at room temperature overnight.The reaction was quenched with aqueous 1 N HCl (25 mL), until thesolution reached pH 1. The reaction mixture was extracted withdichloromethane. The combined organic layers were dried over Na₂SO₄,filtered and concentrated to a brown solid. The crude was dissolved intoluene (10 mL) and the solution was treated with p-toluenesulfonic acidmonohydrate (458 mg, 2.40 mmol). The resulting reaction mixture was thenheated to reflux under nitrogen for 2 h. The reaction was cooled down toroom temperature, poured into water and extracted with ethyl acetate(400 mL). The organic layer was separated then washed with water, brine,dried over Na₂SO₄, filtered and concentrated to an off-white solid. Thecrude product was purified by recrystallization from ethyl acetate toafford the desired product (145 mg, 27%) as a light yellow solid: ¹H NMR(500 MHz, DMSO-d₆) δ 13.25 (br s, 1H), 9.37 (d, J=1.9 Hz, 1H), 8.82 (d,J=1.9 Hz, 1H), 8.06 (dd, J=7.2, 0.9 Hz, 1H), 7.94 (dd, J=7.8, 0.9 Hz,1H), 2.87 (t, J=7.9 Hz, 1H); MS (ESI+) m/z 247 (M+H).

Step B: A mixture of 2-(thiazol-4-yl)benzoxazole-4-carboxylic acid (80mg, 0.32 mmol), 1-ethyl-3-(3-dimethylaminopropyl)carbodiimidehydrochloride (122 mg, 0.64 mmol), 1-hydroxybenzotriazole (86 mg, 0.64mmol) and (S)-(−)-3-aminoquinuclidine dihydrochloride (81 mg, 0.41 mmol)in DMF (5 mL) was stirred at room temperature for 10 min, thentriethylamine (0.13 mL, 1.0 mmol) was added. The resulting reactionmixture was stirred at room temperature overnight. The mixture wasdiluted with dichloromethane (100 mL), and then washed with a saturatedsolution of sodium bicarbonate. The aqueous layer was further extractedwith dichloromethane (2×50 mL). The combined organics were washed withwater (5×25 mL), brine (25 mL), dried (Na₂SO₄), filtered andconcentrated. The crude material was purified by column chromatography(silica gel, 90:9:1 dichloromethane/methanol/concentrated ammoniumhydroxide) and recrystallization from acetonitrile to afford the desiredproduct (41 mg, 37%) as a light yellow solid: ¹H NMR (500 MHz, CDCl₃) δ9.52 (d, J=7.1 Hz, 1H), 9.03 (d, J=2.1 Hz, 1H), 8.35 (d, J=2.1 Hz, 1H),8.22 (dd, J=7.8, 1.0 Hz, 1H), 7.78 (dd, J=8.1, 1.0 Hz, 1H), 7.53 (t,J=7.9 Hz, 1H), 4.42-4.35 (m, 1H), 3.60-3.53 (m, 1H), 3.25-3.05 (m, 2H),3.02-2.90 (m, 3H), 2.28-2.10 (m, 2H), 1.87-1.80 (m, 2H), 1.75-1.67 (m,1H); MS (ESI+) m/z 355 (M+H).

Step C: To a solutionof(S)-N-(1-azabicyclo[2.2.2]oct-3-yl)-2-(4-methylthiazol-5-yl)benzoxazole-4-carboxamide(41 mg, 0.12 mmol) in methanol (2.0 mL) was added a solution of HCl indiethyl ether (1 N, 0.32 mL, 0.32 mmol) at room temperature slowly. Thereaction mixture was diluted with diethyl ether. The resulting solid wasfiltered and washed with diethyl ether to afford(S)-N-(1-azabicyclo[2.2.2]oct-3-yl)-2-(thiazole-4-yl)benzoxazole-4-carboxamidehydrochloride (37 mg, 82%) as a light yellow solid: ¹H NMR (500 MHz,DMSO-d₆) δ 10.20 (s, 1H), 9.41 (d, J=1.8 Hz, 1H), 9.31 (d, J=6.5 Hz,1H), 8.90 (d, J=2.2 Hz, 1H), 8.07 (dd, J=7.8, 1.0 Hz, 1H), 7.78 (dd,J=8.1, 1.0 Hz, 1H), 7.60 (t, J=8.0 Hz, 1H), 4.56-4.44 (m, 1H), 3.77 (t,J=11.6 Hz, 1H), 3.45-3.20 (m, 5H), 2.28-2.20 (m, 2H), 2.02-1.90 (m, 3H);MS (ESI+) m/z 355 (M+H); HPLC 95.0% (AUC), t_(R)=11.90 min.

Example 144 Preparation ofN-(9-Methyl-9-azabicyclo[3.3.1]non-3-yl)-2-(thiazol-4-yl)benzoxazole-4-carboxamideHydrochloride

Step A: A mixture of 2-(thiazol-4-yl)benzoxazole-4-carboxylic acid (60mg, 0.24 mmol), 1-ethyl-3-(3-dimethylaminopropyl)carbodiimidehydrochloride (92 mg, 0.48 mmol), 1-hydroxybenzotriazole (65 mg, 0.48mmol) and 3-amino-9-methyl-9-azabicyclo[3.3.1]nonane dihydrochloride (68mg, 0.30 mmol) in DMF (2 mL) was stirred at room temperature for 10 min,then triethylamine (0.10 mL, 0.73 mmol) was added. The resultingreaction mixture was stirred at room temperature overnight. The mixturewas diluted with ethyl acetate and then washed with a saturated solutionof sodium bicarbonate. The aqueous layer was further extracted withdichloromethane (2×50 mL). The combined organic layers were washed withbrine (2×25 mL), dried (Na₂SO₄), filtered and concentrated. The crudematerial was purified by column chromatography (silica gel, 90:9:1dichloromethane/methanol/concentrated ammonium hydroxide) andrecrystallization from acetonitrile to afford the desired product (51mg, 56%) as a light yellow solid: ¹H NMR (500 MHz, CDCl₃) δ 9.14 (br s,1H), 9.03 (d, J=2.0 Hz, 1H), 8.40 (d, J=2.0 Hz, 1H), 8.22 (dd, J=7.8,1.0 Hz, 1H), 7.76 (dd, J=8.0, 0.9 Hz, 1H), 7.51 (t, J=7.9 Hz, 1H),4.70-4.61 (m, 1H), 3.35-3.28 (m, 2H), 2.75-2.66 (m, 2H), 2.68 (s, 3H),2.40-2.30 (m, 1H), 2.24-2.12 (m, 2H), 1.97-1.85 (m, 2H), 1.70-1.61 (m,1H), 1.50-1.41 (m, 2H); MS (ESI+) m/z 383 (M+H).

Step B: To a solution of(S)-N-(1-azabicyclo[2.2.2]oct-3-yl)-2-(thiazol-4-yl)benzoxazole-4-carboxamide(51 mg, 0.13 mmol) in methanol (2.0 mL) was added a solution of HCl indiethyl ether (1 N, 0.26 mL, 0.26 mmol) at room temperature slowly. Thereaction mixture was diluted with diethyl ether. The resulting solid wasfiltered and washed with diethyl ether to affordN-(9-methyl-9-azabicyclo[3.3.1]non-3-yl)-2-(thiazol-4-yl)benzoxazole-4-carboxamidehydrochloride (32 mg, 59%) as an off-white solid: ¹H NMR (500 MHz,DMSO-d₆) δ 10.26 (br s, 0.3H), 9.57 (br s, 0.7H), 9.42-9.39 (m, 1H),9.28 (d, J=6.6 Hz, 0.3H), 8.92-8.90 (m, 1.4H), 8.84-8.81 (m, 0.3H),8.10-8.05 (m, 1H), 8.00-7.95 (m, 1H), 7.65-7.55 (m, 1H), 4.70-4.60 (m,0.7H), 4.45-4.35 (m, 0.3H), 3.70-3.65 (m, 1.4H), 3.60-3.55 (m, 0.6H),3.90-3.80 (m, 3H), 3.75-3.55 (m, 2H), 2.30-2.05 (m, 3H), 1.95-1.85 (m,3H), 1.65-1.50 (m, 2H); MS (ESI+) m/z 383 (M+H); HPLC 97.6% (AUC),t_(R)=12.47 min.

Example 145 Preparation of(S)-N-(1-Azabicyclo[2.2.2]oct-3-yl)-2-(2-oxo-1,2-dihydropyridin-3-yl)benzoxazole-4-carboxamide

Step A: To an ice-cold suspension of 2-methoxynicotinic acid (678 mg,4.43 mmol) in dichloromethane (10 mL) was added oxalyl chloride (0.42mL, 4.99 mmol) dropwise. Then the ice-water bath was removed and thereaction mixture was stirred for 2 h. To the above solution was added2-amino-3-hydroxybenzoic acid hydrobromide (1.0 g, 4.43 mmol) followedby the addition of triethylamine (2.5 mL, 17.7 mmol). The resultingreaction mixture was stirred at room temperature overnight. The reactionwas quenched with water (50 mL) and pH was adjusted to 7. The reactionmixture was extracted with dichloromethane. The aqueous layer wasextracted with dichloromethane (2×100 mL). The combined organic layerswere dried over Na₂SO₄, filtered and concentrated to afford a yellowsolid. The crude was dissolved in toluene (5 mL) and the solution wastreated with p-toluenesulfonic acid monohydrate (0.98 g, 4.99 mmol). Thereaction mixture was then heated to reflux under nitrogen for 4.5 h. Alight yellow solid was precipitated and the solid was separated, washedwith dichloromethane to afford the desired product (448 mg, 43%) as ayellow solid: ¹H NMR (500 MHz, DMSO-d₆) 12.55 (br s, 1H), 8.43 (dd,J=5.0, 2.2 Hz, 1H), 8.01 (dd, J=8.1, 1.0 Hz, 1H), 7.90 (dd, J=7.8, 1.0Hz, 1H), 7.75 (dd, J=6.3, 2.2 Hz, 1H), 7.51-7.48 (m, 1H): MS (ESI+) m/z256 (M+H).

Step B: A mixture of2-(2-oxo-1,2-dihydropyridin-3-yl)benzoxazole-4-carboxylic acid (102 mg,0.40 mmol), 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride(153 mg, 0.80 mmol), 1-hydroxybenzotriazole (108 mg, 0.80 mmol) and(S)-(−)-3-aminoquinuclidine dihydrochloride (99 mg, 0.49 mmol) in DMF (5mL) was stirred at room temperature for 10 min, then triethylamine (0.22mL, 1.6 mmol) was added. The resulting reaction mixture was stirred atroom temperature overnight. The mixture was diluted with dichloromethaneand then washed with a saturated solution of sodium bicarbonate. Theaqueous layer was further extracted with dichloromethane (3×100 mL). Thecombined organic layers were washed with brine (2×50 mL), dried(Na₂SO₄), filtered and concentrated. The crude material was purified bycolumn chromatography (silica gel, 90:9:1dichloromethane/methanol/concentrated ammonium hydroxide) andcrystallizations from acetonitrile to afford(S)-N-(1-azabicyclo[2.2.2]oct-3-yl)-2-(2-oxo-1,2-dihydropyridin-3-yl)benzoxazole-4-carboxamide(69 mg, 54%) as yellow solid: ¹H NMR (500 MHz, CDCl₃) δ 9.80 (d, J=7.5Hz, 1H), 8.49 (dd, J=7.3, 2.1 Hz, 1H), 8.18 (dd, J=7.8, 0.9 Hz, 1H),7.80 (dd, J=6.3, 2.1 Hz, 1H), 7.72 (dd, J=8.2, 0.9 Hz, 1H), 7.48 (t,J=7.9 Hz, 1H), 6.51 (dd, J=7.2, 4.0 Hz, 1H), 4.42-4.36 (m, 1H),3.57-3.50 (m, 1H), 3.33-3.24 (m, 2H), 3.08-3.01 (m, 1H), 2.99-2.94 (m,3H), 2.25-2.20 (m, 2H), 1.84-1.80 (m, 2H), 1.65-1.58 (m, 1H); MS (ESI+)m/z 365 (M+H); HPLC >99% (AUC), t_(R)=11.31 min.

Example 146 Preparation ofN-(9-Methyl-9-azabicyclo[3.3.1]non-3-yl)-2-(2-oxo-1,2-dihydropyridin-3-yl)benzoxazole-4-carboxamide

A mixture of 2-(2-oxo-1,2-dihydropyridin-3-yl)benzoxazole-4-carboxylicacid (102 mg, 0.40 mmol), 1-ethyl-3-(3-dimethylaminopropyl)carbodiimidehydrochloride (153 mg, 0.80 mmol), 1-hydroxybenzotriazole (108 mg, 0.80mmol) and 3-amino-9-methyl-9-azabicyclo[3.3.1]nonane dihydrochloride(135 mg, 0.49 mmol) in DMF (5 mL) was stirred at room temperature for 10min, then triethylamine (0.22 mL, 1.60 mmol) was added. The resultingreaction mixture was stirred at room temperature overnight. The mixturewas diluted with dichloromethane and then washed with a saturatedsolution of sodium bicarbonate. The aqueous layer was further extractedwith dichloromethane (3×100 mL). The combined organic layers were washedwith water (2×50 mL), brine (2×50 mL), dried (Na₂SO₄), filtered andconcentrated. The crude material was purified by preparative HPLC toaffordN-(9-methyl-9-azabicyclo[3.3.1]non-3-yl)-2-(2-oxo-1,2-dihydropyridin-3-yl)benzoxazole-4-carboxamide(21 mg, 13%) as a yellow solid: ¹H NMR (500 MHz, CDCl₃) δ 8.94 (br s,1H), 8.53 (dd, J=7.3, 1.7 Hz, 1H), 8.22 (d, J=7.7 Hz, 1H), 7.76-7.69 (m,2H), 7.48 (t, J=7.9 Hz, 1H), 6.58 (t, J=6.7 Hz, 1H), 4.64-4.55 (m, 1H),3.15-3.10 (m, 2H), 2.68-2.62 (m, 2H), 2.54 (s, 3H), 2.15-1.95 (m, 3H),1.60-1.47 (m, 4H), 1.15-1.10 (m, 2H); MS (ESI+) m/z 393(M+H); HPLC >99%(AUC), t_(R)=12.23 min.

Example 147 Preparation ofN-(9-Methyl-9-azabicyclo[3.3.1]non-3-yl)-2-(2-morpholinophenyl)benzoxazole-4-carboxamideMaleate

Step A: A dry flask was charged withN-(9-methyl-9-azabicyclo[3.3.1]non-3-yl)-2-(2-bromophenyl)benzoxazole-4-carboxamide(100 mg, 0.22 mmol), morpholine (0.10 mL, 0.66 mmol), Pd(OAc)₂ (14 mg,0.06 mmol), xantphos (46 mg, 0.08 mmol), cesium carbonate (100 mg, 0.31mmol) and 1,4-dioxane (1.0 mL). The mixture was degassed with argon. Theresulting reaction mixture was heated at 100° C. under argon for 12 h.The reaction mixture was cooled to room temperature and extracted withmethylene chloride. The combined organic layers were washed with water,brine, dried over sodium sulfate and concentrated to give a yellowsolid. The crude was purified by preparative TLC to afford the desiredamide (54 mg, 53%) as a light yellow solid: ¹H NMR (500 MHz, CDCl₃) δ9.05 (br s, 1H), 8.22 (d, J=7.7 Hz, 1H), 8.02 (d, J=7.8 Hz, 1H), 7.72(d, J=7.8 Hz, 1H), 7.58-7.52 (m, 1H), 7.48 (t, J=8.1 Hz, 1H), 7.21-7.15(m, 2H), 4.67-4.56 (m, 1H), 3.85 (t, J=4.5 Hz, 4H), 3.30-3.10 (m, 2H),3.04 (t, J=4.5 Hz, 4H), 2.75-2.50 (m, 5H), 2.25-1.95 (m, 3H), 1.70-1.45(m, 3H), 1.30-1.10 (m, 2H); MS (ESI+) m/z 461 (M+H).

Step B: To a solution of the benzoxazole carboxamide from step A (31 mg,0.07 mmol) in methanol (0.5 mL) was added maleic acid (7.4 mg, 0.06mmol) and acetonitrile (4 mL). The resulting solution was freezed anddried to affordN-(9-methyl-9-azabicyclo[3.3.1]non-3-yl)-2-(2-morpholinophenyl)benzoxazole-4-carboxamidemaleate (38 mg, quantitative) as a light green solid: ¹H NMR (300 MHz,CDCl₃) δ 12.07 (br s, 0.4H), 11.49 (br s, 0.6H), 9.56 (d, J=10.0 Hz,0.4H), 9.42 (d, J=10.0 Hz, 0.6H), 8.24-8.15 (m, 1H), 8.00 (dd, J=12.9,2.8 Hz, 0.6H), 7.92 (dd, J=12.9, 2.8 Hz, 0.4H), 7.83-7.72 (m, 1H),7.62-7.45 (m, 3H), 7.14 (t, J=7.8 Hz, 2H), 6.36 (s, 2H), 4.70-4.55 (m,1H), 3.88-3.80 (m, 4H), 3.75-3.64 (m, 2H), 3.05-3.00 (m, 4H), 2.96-2.90(m, 5H), 2.87-2.75 (m, 1H), 2.65-2.40 (m, 3H), 2.20-1.65 (m, 4H); MS(ESI+) m/z 461 (M+H); HPLC 97.2% (AUC), t_(R)=12.72 min.

Example 148 Preparation ofN-(9-Methyl-9-azabicyclo[3.3.1]non-3-yl)-2-[2-(4-methylpiperazin-1-yl)phenyl]benzoxazole-4-carboxamideMaleate

Step A: A dry flask was charged withN-(9-methyl-9-azabicyclo[3.3.1]non-3-yl)-2-(2-bromophenyl)benzoxazole-4-carboxamide(100 mg, 0.22 mmol), 1-methylpiperazine (0.10 mL, 0.88 mmol), Pd(OAc)₂(14 mg, 0.06 mmol), xantphos (46 mg, 0.08 mmol), cesium carbonate (100mg, 0.31 mmol) and 1,4-dioxane (2.5 mL). The mixture was degassed withargon. The resulting reaction mixture was heated at 100° C. under argonfor 12 h. The reaction mixture was then cooled to room temperature andextracted with methylene chloride. The combined organic layers werewashed with water and brine, dried over sodium sulfate and concentrated.The crude was purified by preparative TLC to afford the amide (53 mg,51%) as a yellow solid: ¹H NMR (500 MHz, CDCl₃) δ 9.08 (br s, 1H), 8.22(d, J=7.7 Hz, 1H), 7.97 (d, J=7.3 Hz, 1H), 7.72 (d, J=8.1 Hz, 1H),7.55-7.50 (m, 1H), 7.47 (t, J=8.1 Hz, 1H), 7.20-7.16 (m, 2H), 4.67-4.56(m, 1H), 3.24-3.11 (m, 1H), 3.07 (t, J=4.7 Hz, 4H), 2.70-2.50 (m, 9H),2.35 (s, 3H), 2.08-1.95 (m, 2H), 1.67-1.45 (m, 5H), 1.20-1.10 (m, 2H);MS (ESI+) m/z 474 (M+H).

Step B: To a solution of the benzoxazole carboxamide (41 mg, 0.09 mmol)in methanol (1.0 mL) was added maleic acid (9 mg, 0.8 mmol) andacetonitrile (4 mL). The resulting solution was freezed and dried toaffordN-(9-methyl-9-azabicyclo[3.3.1]non-3-yl)-2-[2-(4-methylpiperazin-1-yl)phenyl]benzoxazole-4-carboxamidemaleate (68 mg, quantitative) as a brown solid: ¹H NMR (300 MHz, CDCl₃)δ 11.62 (br s, 0.2H), 10.75 (br s, 0.8H), 9.43 (d, J=10.4 Hz, 0.2H),9.32 (d, J=10.4 Hz, 0.8H), 8.25-8.15 (m, 1H), 8.07 (dd, J=8.1, 1.6 Hz,0.8H), 7.92 (dd, J=8.1, 1.6 Hz, 0.2H), 7.83-7.75 (m, 1H), 7.62-7.45 (m,2H), 7.35-7.28 (m, 2H), 6.36 (s, 3H), 4.90-4.75 (m, 0.8H), 4.65-4.55 (m,0.2H), 3.80-3.55 (m, 6H), 3.50-3.20 (m, 4H), 3.05-2.90 (m, 6H),2.75-2.50 (m, 5H), 2.20-1.98 (m, 2H), 1.87-1.65 (m, 3H); MS (ESI+) m/z474 (M+H); HPLC >99% (AUC), t_(R)=12.17 min.

Example 149 Preparation ofN-(9-Methyl-9-azabicyclo[3.3.1]non-3-yl)-2-(2-isopropylphenyl)benzoxazole-4-carboxamideHydrochloride

Step A: To a solution of 2-bromoisopropylbenzene (5.00 g, 25.1 mmol) inanhydrous tetrahydrofuran (40 mL) at −78° C., was added n-BuLi (2.5 Msolution in hexanes, 25 mL, 62 mmol) dropwise. The reaction mixture wasstirred at −78° C. for 2 h and then warmed to 0° C. CO₂ was bubbled intothe reaction mixture for 40 min and then the reaction was quenched witha saturated solution of sodium carbonate (100 mL). The aqueous layer wasseparated and washed with diethyl ether (2×150 mL). The aqueous layerwas treated with 6 N HCl and extracted with dichloromethane (2×250 mL).The combined organic layers were washed with brine (150 mL), dried oversodium sulfate, filtered and concentrated to afford the desired acid(546 mg, 13%) as a light yellow semi-solid: ¹H NMR (500 MHz, CDCl₃) δ10.48 (br s, 1H), 7.92 (dd, J=7.9, 1.4 Hz, 1H), 7.52-7.49 (m, 1H),7.46-7.42 (m, 1H), 7.28-7.20 (m, 1H), 3.95-3.85 (m, 1H), 1.28 (d, J=6.9Hz, 6H).

Step B: To an ice-coold suspension of 2-isopropylbenzoic acid (546 mg,3.33 mmol) in dichloromethane (20 mL) was added oxalyl chloride (0.18mL, 3.3 mmol) dropwise, followed by few drops of anhydrous DMF. Afterthe ice-water bath was removed, the mixture was stirred for 1 h. To theabove solution was added 2-amino-3-hydroxybenzoic acid hydrobromide(0.78 g, 3.3 mmol) followed by triethylamine (1.95 mL, 14.0 mmol). Theresulting reaction mixture was stirred at room temperature overnight.The reaction was quenched with 1 N HCl (50 mL) and extracted withdichloromethane. The aqueous layer was further extracted withdichloromethane (2×50 mL). The combined organic layers were dried overNa₂SO₄, filtrated and concentrated to afford a yellow solid. The crudewas dissolved in toluene (5 mL) and the solution was treated withp-toluenesulfonic acid monohydrate (1.06 g, 5.60 mmol). The reactionmixture was then heated to reflux under nitrogen for 6 h. The reactionwas cooled down to room temperature, poured into water and extractedwith ethyl acetate. The organic layer was separated, washed with waterand brine, dried over Na₂SO₄, filtered and concentrated. The crudeproduct was purified by column chromatography (silica gel, 9:1 to 3:1ethyl acetate/methanol) to afford the desired acid (310 mg, 33%) as ayellow solid: ¹H NMR (500 MHz, DMSO-d₆) δ 13.06 (br s, 1H), 7.98-7.90(m, 2H), 7.86 (d, J=7.6 Hz, 1H), 7.63-7.56 (m, 2H), 7.47 (t, J=7.9 Hz,1H), 7.45-7.35 (m, 1H), 4.00-3.92 (m, 1H), 1.25 (d, J=7.6 Hz, 6H); MS(ESI+) m/z 282 (M+H).

Step C: A mixture of the 2-(2-isopropylphenyl)benzoxazole-4-carboxylicacid from Step B (150 mg, 0.53 mmol),3-amino-9-methyl-9-azabicyclo[3.3.1]nonane dihydrochloride (150 mg, 0.66mmol), 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (202mg, 1.06 mmol), 1-hydroxybenzotriazole (143 mg, 1.06 mmol) and DMF (5mL) was stirred under nitrogen at room temperature for 10 min, and thentriethylamine (0.30 mL, 2.1 mmol) was added. The resulting reactionmixture was stirred at room temperature overnight, and then quenchedwith a saturated solution of sodium bicarbonate and extracted withmethylene chloride. The combined organic layers were washed with brine,dried (Na₂SO₄), filtered and concentrated. The crude material waspurified by column chromatography (silica gel, 90:9:1dichloromethane/methanol/concentrated ammonium hydroxide) to afford thedesired amide (201 mg, 90%) as an off-white solid: ¹H NMR (500 MHz,CDCl₃) δ 8.95 (br s, 1H), 8.22 (d, J=7.6 Hz, 1H), 8.12-8.05 (m, 1H),7.72 (d, J=7.6 Hz, 1H), 7.60-7.54 (m, 2H), 7.48 (t, J=7.8 Hz, 1H),7.42-7.35 (m, 1H), 4.75-4.60 (m, 1H), 4.35-4.20 (m, 1H), 3.30-3.10 (m,2H), 2.75-2.50 (m, 5H), 2.20-1.95 (m, 3H), 1.70-1.50 (m, 3H), 1.38 (d,J=6.9 Hz, 6H), 1.20-1.00 (m, 2H); MS (ESI+) m/z 418 (M+H).

Step D: To a solution of the amide from Step C (200 mg, 0.53 mmol) indichloromethane (2.0 mL) was added a solution of HCl in diethyl ether (1N, 1.0 mL, 1.0 mmol) at room temperature slowly. The reaction mixturewas diluted with diethyl ether. The resulting solid was filtered andwashed with diethyl ether to affordN-(9-methyl-9-azabicyclo[3.3.1]non-3-yl)-2-(2-isopropylphenyl)benzoxazole-4-carboxamidehydrochloride (214 mg, quantitative) as a white solid: ¹H NMR (500 MHz,CDCl₃) δ 12.22 (br s, 0.4H), 11.88 (br s, 0.6H), 9.38 (m, 0.6H), 9.28(d, J=5.8 Hz, 0.4H), 8.22 (d, J=7.8 Hz, 0.4H), 8.17 (d, J=7.8 Hz, 0.6H),8.01 (d, J=7.7 Hz, 0.6H), 7.97 (d, J=7.7 Hz, 0.4H), 7.79 (d, J=8.1 Hz,0.4H), 7.75 (d, J=8.1 Hz, 0.6H), 7.62-7.48 (m, 3H), 7.40-7.30 (m, 1H),4.95-4.80 (m, 0.6H), 4.70-4.60 (m, 0.4H), 4.05-3.90 (m, 1H), 3.70-3.52(m, 2H), 3.00-2.75 (m, 5H), 2.65-2.50 (m, 2H), 2.20-2.05 (m, 1H),1.95-1.65 (m, 5H), 1.39 (d, J=6.7 Hz, 3H), 1.35 (d, J=6.7 Hz, 3H); MS(ESI+) m/z 418 (M+H); HPLC >99% (AUC), t_(R)=13.14 min.

Example 150 Preparation of(S)-N-(1-Azabicyclo[2.2.2]oct-3-yl)-2-(2-isopropylphenyl)benzoxazole-4-carboxamideHydrochloride

Step A: A mixture of 2-(2-isopropylphenyl)benzoxazole-4-carboxylic acid(150 mg, 0.53 mmol), 1-ethyl-3-(3-dimethylaminopropyl)carbodiimidehydrochloride (202 mg, 1.06 mmol), 1-hydroxybenzotriazole (143 mg, 1.06mmol), (S)-(−)-3-aminoquinuclidine dihydrochloride (130 mg, 0.66 mmol)and DMF (5 mL) was stirred at room temperature for 10 min, thentriethylamine (0.30 mL, 0.66 mmol) was added. The resulting reactionmixture was stirred at room temperature for 12 h. The reaction mixturewas diluted with ethyl acetate (50 mL), and then treated with asaturated solution of sodium bicarbonate. The organic layer was isolatedand the aqueous layer was further extracted with ethyl acetate (2×50mL). The combined organics were washed with water (2×25 mL) and brine(2×25 mL), dried (Na₂SO₄), filtered and concentrated. The crude materialwas purified by semi-preparative HPLC to afford the desired amide (198mg, 96%) as an off-white solid: ¹H NMR (500 MHz, CDCl₃) δ 9.24 (d, J=6.4Hz, 1H), 8.22 (dd, J=7.8, 1.0 Hz, 1H), 8.12 (dd, J=7.9, 1.0 Hz, 1H),7.74 (dd, J=8.1, 1.0 Hz, 1H), 7.59-7.50 (m, 2H), 7.48 (t, J=7.9 Hz, 1H),7.41-7.35 (m, 1H), 4.40-4.30 (m, 1H), 4.25-4.15 (m, 1H), 3.60-3.50 (m,1H), 3.10-2.90 (m, 4H), 2.81 (dd, J=13.8, 4.1 Hz, 1H), 2.20-2.15 (m,1H), 2.02-1.92 (m, 1H), 1.85-1.75 (m, 2H), 1.65-1.54 (m, 1H), 1.36 (d,J=3.5 Hz, 3H), 1.34 (d, J=3.5 Hz, 3H); MS (ESI+) m/z 390 (M+H).

Step B: To a solution of the benzoxazole carboxamide from Step A (250mg, 0.49 mmol) in dichloromethane (2.0 mL) was added a solution of HClin diethyl ether (1 N, 1.0 mL, 1.0 mmol) at 0° C. slowly. The reactionmixture was diluted with diethyl ether. The resulting solid was filteredand washed with diethyl ether to afford(S)-N-(1-azabicyclo[2.2.2]oct-3-yl)-2-(2-isopropylphenyl)benzoxazole-4-carboxamidehydrochloride (209 mg, quantitative) as a white solid: ¹H NMR (500 MHz,CDCl₃) δ 11.93 (br s, 1H), 9.46 (br s, 1H), 8.20 (d, J=7.6 Hz, 1H),8.05-7.95 (m, 1H), 7.81 (d, J=7.6 Hz, 1H), 7.60-7.50 (m, 3H), 7.45-7.35(m, 1H), 4.70-4.60 (m, 1H), 4.05-3.85 (m, 2H), 3.55-3.15 (m, 5H),2.60-2.50 (m, 1H), 2.43-2.00 (m, 4H), 1.32-1.29 (m, 6H); MS (ESI+) m/z390 (M+H); HPLC >99% (AUC), t_(R)=12.64 min.

Compound Affinity for the 5-HT₃ Receptor

In order to evaluate the relative affinity of the various compounds forthe 5-HT₃ receptor, N1E-155 cell lines were developed to express thetarget protein. For binding, these cells were homogenized, centrifugedand washed with buffer (20 mM HEPES, 150 mM NaCl, pH 7.4) then suspendedin 0.5 mL of buffer and [³H]-GR65630 added at a concentration of3.5×10⁻¹⁰ M. An initial single concentration of 10⁻⁷ M of the testcompound was then added. Incubation was carried out at room temperaturefor 60 minutes at 25° C. then was terminated by rapid removal of theincubation medium. Radioactivity was assessed using liquid scintillationspectrophotometry after exposure to scintillation cocktail for at leastthree hours. Compounds displaying greater than 75% inhibition ofradioligand binding at 10⁻⁷ M were then resubmitted to the aboveprotocol using the following range of test compound concentrations: 10⁻⁹M, 10⁻⁸ M, 3×10⁻⁸ M, 10⁻⁷M, 3×10⁻⁷ M and 10⁻⁶ M. Competition curves werethen plotted and IC₅₀ determinations made using non-linear regressionanalysis. Ki values were then calculated from the Cheng-Prusoffequation. In all of the above binding studies the non-specificdeterminant was MDL-72222 (1.0 μM). Compounds in the examples above all(with the exceptions noted below) exhibited either greater than 30%inhibition at 100 nM or K_(i) below 300 nM in one or the other of mouseor human 5-HT₃ receptor binding. However, compounds in which: (1) Ar is2-pyridinyl and 3-pyridinyl, except when R⁴ is methylazabicyclo[3.3.1]nonane; (2) Ar is phenyl and R⁴ is1-azabicyclo[2.2.2]oct-3-yl, and R² is chloro; and (3) Ar is phenyl orphenyl substituted with halogen, R⁴ is 1-azabicyclo[2.2.2]oct-3-yl andall of R¹, R² and R³ are H; show binding less than 30% at 100 nM

Bezold-Jarisch Assay in vivo. In order to demonstrate functionalantagonism of 5-HT3 receptors, certain compounds (Table 1) wereevaluated for their ability to inhibit serotonin induced bradycardia invivo in the mouse [Saxena, P. R. and Lawang, A. A comparison ofcardiovascular and smooth muscle effects of 5-hydroxytryptamine and5-carboxamidotryptamine, a selective agonist of 5-HT1 receptors. Arch.Int. Pharmacodyn. 277: 235-252, 1985]. Test substances and vehicle [2%Tween 80] were each administered orally (30 mg/kg) to a group of 5 maleor female CD-1 (Crl.) mice each weighing 24±2 g. A dosing volume of 10mL/kg was used. Sixty minutes later, 5-HT (0.5 mg/kg IV)-inducedbradycardia was recorded in pentobarbital (80 mg/kg IP, given 10 minutesbefore 5-HT)-anesthetized animals. TABLE 1 % Example InhibitionSTRUCTURE number in vivo

40

88

62

The compounds of the invention may be administered orally or viainjection at a dose from 0.001 to 2500 mg/kg per day. The dose range foradult humans is generally from 0.005 mg to 10 g/day. Tablets or otherforms of presentation provided in discrete units may convenientlycontain an amount of compound of the invention which is effective atsuch dosage or as a multiple of the same, for instance, units containing5 mg to 500 mg, usually around 10 mg to 200 mg. The precise amount ofcompound administered to a patient will be the responsibility of theattendant physician. However, the dose employed will depend on a numberof factors, including the age and sex of the patient, the precisedisorder being treated, and its severity. Also, the route ofadministration may vary depending on the condition and its severity.

As used herein, and as would be understood by the person of skill in theart, the recitation of “a compound” is intended to include salts,solvates and inclusion complexes of that compound. The term “solvate”refers to a compound of Formula I in the solid state, wherein moleculesof a suitable solvent are incorporated in the crystal lattice. Asuitable solvent for therapeutic administration is physiologicallytolerable at the dosage administered. Examples of suitable solvents fortherapeutic administration are ethanol and water. When water is thesolvent, the solvate is referred to as a hydrate. In general, solvatesare formed by dissolving the compound in the appropriate solvent andisolating the solvate by cooling or using an antisolvent. The solvate istypically dried or azeotroped under ambient conditions. Inclusioncomplexes are described in Remington: The Science and Practice ofPharmacy 19th Ed. (1995) volume 1, page 176-177, which is incorporatedherein by reference. The most commonly employed inclusion complexes arethose with cyclodextrins, and all cyclodextrin complexes, natural andsynthetic, are specifically encompassed within the claims.

The term “pharmaceutically acceptable salt” refers to salts preparedfrom pharmaceutically acceptable non-toxic acids or bases includinginorganic acids and bases and organic acids and bases. When thecompounds of the present invention are basic, salts may be prepared frompharmaceutically acceptable non-toxic acids including inorganic andorganic acids. Suitable pharmaceutically acceptable acid addition saltsfor the compounds of the present invention include acetic,benzenesulfonic (besylate), benzoic, camphorsulfonic, citric,ethenesulfonic, fumaric, gluconic, glutamic, hydrobromic, hydrochloric,isethionic, lactic, maleic, malic, mandelic, methanesulfonic, mucic,nitric, pamoic, pantothenic, phosphoric, succinic, sulfuric, tartaricacid, p-toluenesulfonic, and the like. When the compounds contain anacidic side chain, suitable pharmaceutically acceptable base additionsalts for the compounds of the present invention include metallic saltsmade from aluminum, calcium, lithium, magnesium, potassium, sodium andzinc or organic salts made from lysine, N,N′-dibenzylethylenediamine,chloroprocaine, choline, diethanolamine, ethylenediamine, meglumine(N-methylglucamine) and procaine.

The term “preventing” as used herein refers to administering amedicament beforehand to forestall or obtund an attack. The person ofordinary skill in the medical art (to which the present method claimsare directed) recognizes that the term “prevent” is not an absoluteterm. In the medical art it is understood to refer to the prophylacticadministration of a drug to substantially diminish the likelihood orseriousness of a condition, and this is the sense intended herein.

The graphic representations of racemic, ambiscalemic and scalemic orenantiomerically pure compounds used herein are taken from Maehr J.Chem. Ed. 62, 114-120 (1985): solid and broken wedges are used to denotethe absolute configuration of a chiral element; wavy lines indicatedisavowal of any stereochemical implication which the bond it representscould generate; solid and broken bold lines are geometric descriptorsindicating the relative configuration shown but denoting racemiccharacter; and wedge outlines and dotted or broken lines denoteenantiomerically pure compounds of indeterminate absolute configuration.A simple solid line implies nothing about stereochemistry. For example,a solid line is shown in the graphic for example 139 above, but thecompound of the example is actually a single enantiomer of the Sconfiguration and could have been accurately depicted as

While it may be possible for the compounds of formula (I) to beadministered as the raw chemical, it is preferable to present them as apharmaceutical composition. According to a further aspect, the presentinvention provides a pharmaceutical composition comprising a compound offormula (I) or a pharmaceutically acceptable salt or solvate thereof,together with one or more pharmaceutically carriers thereof andoptionally one or more other therapeutic ingredients. The carrier(s)must be “acceptable” in the sense of being compatible with the otheringredients of the formulation and not deleterious to the recipientthereof.

The formulations include those suitable for oral, parenteral (includingsubcutaneous, intradermal, intramuscular, intravenous andintraarticular), rectal and topical (including dermal, buccal,sublingual and intraocular) administration. The most suitable route maydepend upon the condition and disorder of the recipient. Theformulations may conveniently be presented in unit dosage form and maybe prepared by any of the methods well known in the art of pharmacy. Allmethods include the step of bringing into association a compound offormula (I) or a pharmaceutically acceptable salt or solvate thereof(“active ingredient”) with the carrier which constitutes one or moreaccessory ingredients. In general, the formulations are prepared byuniformly and intimately bringing into association the active ingredientwith liquid carriers or finely divided solid carriers or both and then,if necessary, shaping the product into the desired formulation.Preferred unit dosage formulations are those containing an effectivedose or an appropriate fraction thereof, of the active ingredient.

Formulations of the present invention suitable for oral administrationmay be presented as discrete units such as capsules, cachets or tabletseach containing a predetermined amount of the active ingredient; as apowder or granules; as a solution or a suspension in an aqueous liquidor a non-aqueous liquid; or as an oil-in-water liquid emulsion or awater-in-oil liquid emulsion. The active ingredient may also bepresented as a bolus, electuary or paste.

A tablet may be made by compression or molding, optionally with one ormore accessory ingredients. Compressed tablets may be prepared bycompressing in a suitable machine the active ingredient in afree-flowing form such as a powder or granules, optionally mixed with abinder, lubricant, inert diluent, lubricating, surface active ordispersing agent. Molded tablets may be made by molding in a suitablemachine a mixture of the powdered compound moistened with an inertliquid diluent. The tablets may optionally be coated or scored and maybe formulated so as to provide sustained, delayed or controlled releaseof the active ingredient therein.

Formulations for parenteral administration include aqueous andnon-aqueous sterile injection solutions, which may containanti-oxidants, buffers, bacteriostats and solutes which render theformulation isotonic with the blood of the intended recipient.Formulations for parenteral administration also include aqueous andnon-aqueous sterile suspensions, which may include suspending agents andthickening agents. The formulations may be presented in unit-dose ofmulti-dose containers, for example sealed ampoules and vials, and may bestored in a freeze-dried (lyophilized) condition requiring only theaddition of a sterile liquid carrier, for example saline,phosphate-buffered saline (PBS) or the like, immediately prior to use.Extemporaneous injection solutions and suspensions may be prepared fromsterile powders, granules and tablets of the kind previously described.

Formulations for rectal administration may be presented as a suppositorywith the usual carriers such as cocoa butter or polyethylene glycol.

Formulations for topical administration in the mouth, for examplebuccally or sublingually, include lozenges comprising the activeingredient in a flavored basis such as sucrose and acacia or tragacanth,and pastilles comprising the active ingredient in a basis such asgelatin and glycerin or sucrose and acacia.

It should be understood that in addition to the ingredients particularlymentioned above, the formulations of this invention may include otheragents conventional in the art having regard to the type of formulationin question, for example those suitable for oral administration mayinclude flavoring agents.

Although the foregoing invention has been described in some detail forpurposes of illustration, it will be readily apparent to one skilled inthe art that changes and modifications may be made without departingfrom the scope of the invention described herein.

1. A compound of formula

wherein R¹, R² and R³ are independently selected from hydrogen, halogen,amino, alkylamino, dialkylamino, acylamino, morpholinyl, —O-loweralkyl,hydroxy, loweralkyl, fluoroloweralkyl, —O-lowerfluoroalkyl,methylenedioxy, ethylenedioxy, alkoxy-loweralkyl and hydroxyloweralkyl;R⁴ is a residue chosen from: (i) a saturated nitrogen heterocycle ormethyl-substituted saturated nitrogen heterocycle, in which saidnitrogen is tertiary, said heterocycle containing at least one 5 or6-membered ring; and (ii) an imidazolylalkyl residue wherein theimidazole of said imidazolylalkyl is optionally substituted with up tothree groups chosen from halogen, (C₁-C₄)alkyl, substituted (C₁-C₄)alkyland NH₂; and Ar is chosen from the group consisting of (i) aryl; (ii)heteroaryl; (iii) substituted aryl; (iv) substituted heteroaryl; and (v)dihydroheteroaryl.
 2. A compound according to claim 1 of formula

wherein R¹, R² and R³ are independently selected from hydrogen, halogen,amino, alkylamino, dialkylamino, acylamino, morpholinyl, —O-loweralkyl,hydroxy, loweralkyl, fluoroloweralkyl, —O-lowerfluoroalkyl,methylenedioxy, ethylenedioxy, alkoxy-loweralkyl and hydroxyloweralkyl;

 represents a saturated nitrogen heterocycle or methyl-substitutedsaturated nitrogen heterocycle, in which said nitrogen is tertiary, saidheterocycle containing at least one 5 or 6-membered ring; and Ar ischosen from the group consisting of: (i) aryl; (ii) heteroaryl otherthan 2-pyridinyl and 3-pyridinyl, provided that when

 is methyl azabicyclo[3.3.1]nonane, Ar may additionally be 3-pyridinyl;(iii) aryl substituted with from one to four substitutents chosen fromlower alkoxy, phenoxy, trialkylsilylacetylenyl, anilino, lower alkynyl,lower alkyl, halogen, nitro, cyano, hydroxy, amino, methylenedioxy,alkylamino, dialkylamino, phenyl, heterocyclyl, methylheterocyclyl,methylenedioxy and acylamino; (iv) heteroaryl substituted with one ortwo substitutents chosen from oxo, halogen, and alkyl; and (v)dihydroheteroaryl; with the proviso that, when Ar is phenyl and

 is 1-azabicyclo[2.2.2]oct-3-yl, R² cannot be chloro.
 3. A compound offormula

wherein R¹, R² and R³ are independently selected from hydrogen, halogen,amino, alkylamino, dialkylamino, acylamino, morpholinyl, —O-loweralkyl,hydroxy, loweralkyl, fluoroloweralkyl, —O-lowerfluoroalkyl,methylenedioxy, ethylenedioxy, alkoxy-loweralkyl and hydroxyloweralkyl;R⁴ is a residue chosen from: (i) a saturated nitrogen heterocycle ormethyl-substituted saturated nitrogen heterocycle, in which saidnitrogen is tertiary, said heterocycle containing at least one 5 or6-membered ring; and (ii) an imidazolylalkyl residue wherein theimidazole of said imidazolylalkyl is optionally substituted with up tothree groups chosen from halogen, (C₁-C₄)alkyl, substituted (C₁-C₄)alkyland NH₂; and Ar is chosen from the group consisting of (i) aryl; (ii)heteroaryl; (iii) substituted aryl; (iv) substituted heteroaryl; and (v)dihydroheteroaryl.
 4. A compound according to claim 3 of formula

wherein R¹, R² and R³ are independently selected from hydrogen, halogen,amino, alkylamino, dialkylamino, acylamino, morpholinyl, —O-loweralkyl,hydroxy, loweralkyl, fluoroloweralkyl, —O-lowerfluoroalkyl,methylenedioxy, ethylenedioxy, alkoxy-loweralkyl and hydroxyloweralkyl;

 represents a saturated nitrogen heterocycle or methyl-substitutedsaturated nitrogen heterocycle, in which said nitrogen is tertiary, saidheterocycle containing at least two 6-membered rings; and Ar is chosenfrom the group consisting of (i) aryl; (ii) heteroaryl other than2-pyridinyl and 3-pyridinyl; (iii) aryl substituted with from one tofour substitutents chosen from lower alkoxy, phenoxy,trialkylsilylacetylenyl, anilino, lower alkynyl, lower alkyl, halogen,nitro, cyano, hydroxy, amino, acetylamino, methylenedioxy, alkylamino,dialkylamino, phenyl, heterocyclyl, methylheterocyclyl, methylenedioxyand acylamino; (iv) heteroaryl substituted with one or two substitutentschosen from oxo, halogen, and alkyl; and (v) dihydroheteroaryl; with theproviso that, when

 is 1-azabicyclo[2.2.2]oct-3-yl and all of R¹, R² and R³ are H, Arcannot be phenyl or phenyl substituted with halogen.
 5. A compoundaccording to claim 2 wherein

is chosen from:

wherein m=1, 2, 3 or 4; n=0, 1, 2, 3 or 4; and R⁵ is hydrogen or methyl.6. A compound according to claim 4 wherein

is chosen from:

wherein m=1, 2, 3 or 4; n=0, 1, 2, 3 or 4; and R⁵ is hydrogen or methyl.7. A compound according to claim 5 wherein

is chosen from quinuclidine, tropane, azabicyclo[3.3.1]nonane and methylazabicyclo[3.3.1]nonane.
 8. A compound according to claim 6 wherein

is chosen from quinuclidine, tropane, azabicyclo[3.3.1]nonane and methylazabicyclo[3.3.1]nonane.
 9. A compound according to claim 1 or 3,wherein R¹, R² and R³ are hydrogen.
 10. A compound according to claim 1or 3, wherein one of R¹, R² and R³ is halogen.
 11. A compound accordingto claim 1 or 3, wherein R¹ and R³ are hydrogen and R² is chosen fromamino, halogen, methoxy, hydroxy, acetylamino, and 4-morpholinyl.
 12. Acompound according to claim 1 or 3 wherein Ar is chosen from the groupconsisting of phenyl and phenyl substituted with from 1 to 4 groupsindependently selected from (C₁ to C₄)alkyl, phenyl, phenoxy, halogen,(C₁ to C₄)alkoxy, amino, (C₁ to C₄)alkylamino, di(C₁ to C₄)alkylamino,anilino, heterocyclyl, methylheterocyclyl, methylenedioxy, (C₁ toC₄)acylamino, (C₁ to C₄)alkynyl and nitro.
 13. A compound according toclaim 12 wherein Ar is chosen from the group consisting of phenyl andphenyl substituted with one or two residues chosen independently from(C₁ to C₄)alkyl, 4-methylpiperazinl-yl, morpholin-4-yl, pyridin-4-yl,phenyl, phenoxy, amino, anilino, halogen, methoxy, dimethylamino,methylenedioxy, acetylamino, propyn-1-yl and nitro.
 14. A compoundaccording to claim 1 or 3 wherein Ar is chosen from the group consistingof heteroaryl, dihydroheteroaryl and substituted heteroaryl.
 15. Acompound according to claim 14 wherein Ar is chosen from thiophene,cyclopenta[b]thiophene, furan, thiazole, isoxazole dihydrobenzofuran,benzofuran, pyridine, benzothiophene, 3-pyridine-2-one, and theirmethylated and halogenated congeners.
 16. A compound according to claim1 or 3 chosen from:N-[3-(2-Methylimidazol-1-yl)propyl]-2-phenylbenzoxazole-4-carboxamideN-[2-(2-Methylimidazol-1-yl)ethyl]-2-phenylbenzoxazole-4-carboxamideN-(1-Methylpiperidin-4-yl)-2-phenylbenzoxazole-4-carboxamideN-(9-Methyl-9-azabicyclo[3.3.1]non-3-yl)-2-phenylbenzoxazole-4-carboxamideN-(8-Methyl-8-azabicyclo[3.2.1]oct-3-yl)-2-phenylbenzoxazole-4-carboxamideN-(9-Methyl-9-azabicyclo[3.3.1]non-3-yl)-6-chloro-2-phenylbenzoxazole-4-carboxamideN-(Piperidin-4-yl)-2-phenylbenzoxazole-4-carboxamideN-(1-Azabicyclo[2.2.2]oct-3-yl)-2-phenylbenzoxazole-4-carboxamideN-(1-Methyl-piperidin-4-yl)-6-chloro-2-phenylbenzoxazole-4-carboxamideN-(1-Azabicyclo[2.2.2]oct-3-yl)-6-chloro-2-phenylbenzoxazole-4-carboxamideN-(8-Methyl-8-azabicyclo[3.2.1]oct-3-yl)-6-chloro-2-phenylbenzoxazole-4-carboxamideN-(1-Azabicyclo[2.2.2]oct-3-yl)-2-(4-chlorophenyl)benzoxazole-4-carboxamideN-(9-Methyl-9-azabicyclo[3.3.1]non-3-yl)-2-(4-chlorophenyl)benzoxazole-4-carboxamideN-(1-Azabicyclo[2.2.2]oct-3-yl)-2-(4-methoxyphenyl)benzoxazole-4-carboxamideN-(9-Methyl-9-azabicyclo[3.3.1]non-3-yl)-2-(4-methoxyphenyl)benzoxazole-4-carboxamideN-(9-Methyl-9-azabicyclo[3.3.1]non-3-yl)-2-(4-fluorophenyl)benzoxazole-4-carboxamideN-(1-Azabicyclo[2.2.2]oct-3-yl)-2-(4-fluorophenyl)benzoxazole-4-carboxamideN-(9-Methyl-9-azabicyclo[3.3.1]non-3-yl)-2-phenylbenzoxazole-7-carboxamideN-(1-Methylpiperidin-4-yl)-2-phenylbenzoxazole-7-carboxamideN-(Piperidin-4-yl)-2-phenylbenzoxazole-7-carboxamideN-(1-Azabicyclo[2.2.2]oct-3-yl)-2-phenylbenzoxazole-7-carboxamideN-(8-Methyl-8-azabicyclo[3.2.1]oct-3-yl)-2-phenylbenzoxazole-7-carboxamideN-(1-Azabicyclo[2.2.2]oct-3-yl)-5-chloro-2-phenyl-benzoxazole-7-carboxamideN-(9-Methyl-9-azabicyclo[3.3.1]non-3-yl)-5-chloro-2-phenyl-benzoxazole-7-carboxamideN-(9-Methyl-9-azabicyclo[3.3.1]non-3-yl)-2-(4-fluorophenyl)benzoxazole-7-carboxamideN-(1-Azabicyclo[2.2.2]oct-3-yl)-2-(4-methoxyphenyl)benzoxazole-7-carboxamideN-(9-Methyl-9-azabicyclo[3.3.1]non-3-yl)-2-(4-methoxyphenyl)benzoxazole-7-carboxamideN-(1-Azabicyclo[2.2.2]oct-3-yl)-2-(4-chlorophenyl)benzoxazole-7-carboxamideN-(9-Methyl-9-azabicyclo[3.3.1]non-3-yl)-2-(4-chlorophenyl)benzoxazole-7-carboxamideN-(9-Methyl-9-azabicyclo[3.3.1]non-3-yl)-2-phenylbenzothiazole-7-carboxamide(S)-N-(1-Azabicyclo[2.2.2]oct-3-yl)-6-chloro-2-phenylbenzoxazole-4-carboxamideN-(9-Methyl-3-oxa-9-azabicyclo[3.3.1]non-7-yl)-2-phenylbenzoxazole-4-carboxamideN-(9-Methyl-3-oxa-9-azabicyclo[3.3.1]non-7-yl)-6-chloro-2-phenylbenzoxazole-4-carboxamideN-(1-Azabicyclo[2.2.2]oct-3-yl)-2-(2-methoxyphenyl)benzoxazole-4-carboxamideN-(9-Methyl-9-azabicyclo[3.3.1]non-3-yl)-2-(2-methoxyphenyl)benzoxazole-4-carboxamideHydrochlorideN-(1-Azabicyclo[2.2.2]oct-3-yl)-2-(3-methoxyphenyl)benzoxazole-4-carboxamide(S)-N-(1-Azabicyclo[2.2.2]oct-3-yl)-2-(2-hydroxyphenyl)benzoxazole-4-carboxamideHydrochlorideN-(9-Methyl-9-azabicyclo[3.3.1]non-3-yl)-2-(2-hydroxyphenyl)benzoxazole-4-carboxamideHydrochlorideN-(9-Methyl-9-azabicyclo[3.3.1]non-3-yl)-2-(2-bromophenyl)benzoxazole-4-carboxamideHydrochlorideN-(9-Methyl-9-azabicyclo[3.3.1]non-3-yl)-2-(2-aminophenyl)benzoxazole-4-carboxamideDihydrochlorideN-(9-Methyl-9-azabicyclo[3.3.1]non-3-yl)-2-(biphenyl-2-yl)benzoxazole-4-carboxamideHydrochlorideN-(9-Methyl-9-azabicyclo[3.3.1]non-3-yl)-2-(2-pyridine-4-yl)phenylbenzoxazole-4-carboxamideDihydrochlorideN-(1-Azabicyclo[2.2.2]oct-3-yl)-2-p-tolylbenzoxazole-4-carboxamideN-(9-Methyl-9-azabicyclo[3.3.1]non-3-yl)-2-p-tolylbenzoxazole-4-carboxamideN-(1-Azabicyclo[2.2.2]oct-3-yl)-2-(4-nitrophenyl)benzoxazole-4-carboxamideN-(1-Azabicyclo[2.2.2]oct-3-yl)-2-(4-aminophenyl)benzoxazole-4-carboxamideN-(1-Azabicyclo[2.2.2]oct-3-yl)-2-(4-acetylaminophenyl)benzoxazole-4-carboxamideN-(1-Azabicyclo[2.2.2]oct-3-yl)-2-(4-dimethylaminophenyl)benzoxazole-4-carboxamideN-(9-Methyl-9-azabicyclo[3.3.1]non-3-yl)-2-(4-dimethylaminophenyl)benzoxazole-4-carboxamideN-(9-Methyl-9-azabicyclo[3.3.1]non-3-yl)-2-(2-dimethylaminophenyl)benzoxazole-4-carboxamide(S)-N-(1-Azabicyclo[2.2.2]oct-3-yl)-2-(2-dimethylaminophenyl)benzoxazole-4-carboxamideN-(9-Methyl-9-azabicyclo[3.3.1]non-3-yl)-6-chloro-2-(2-dimethylaminophenyl)benzoxazole-4-carboxamide(S)-N-(1-Azabicyclo[2.2.2]oct-3-yl)-6-chloro-2-(2-dimethylaminophenyl)benzoxazole-4-carboxamideN-(1-Azabicyclo[2.2.2]oct-3-yl)-2-(4-cyanophenyl)benzoxazole-4-carboxamideN-(1-Azabicyclo[2.2.2]oct-3-yl)-2-(4-iodophenyl)benzoxazole-4-carboxamideN-(1-Azabicyclo[2.2.2]oct-3-yl)-2-(4-trimethylsilylethynylphenyl)benzoxazole-4-carboxamideN-(1-Azabicyclo[2.2.2]oct-3-yl)-2-(4-propyn-1-ylphenyl)benzoxazole-4-carboxamideN-(1-Azabicyclo[2.2.2]oct-3-yl)-2-(4-ethynylphenyl)benzoxazole-4-carboxamideN-(1-Azabicyclo[2.2.2]oct-3-yl)-2-biphenyl-4-ylbenzoxazole-4-carboxamideN-(1-Azabicyclo[2.2.2]oct-3-yl)-2-(4-phenoxyphenyl)benzoxazole-4-carboxamideN-(1-Azabicyclo[2.2.2]oct-3-yl)-2-(4-phenylaminophenyl)benzoxazole-4-carboxamideN-(9-Methyl-9-azabicyclo[3.3.1]non-3-yl)-2-benzo[1,3]dioxol-5-ylbenzoxazole-4-carboxamide(S)-N-(1-Azabicyclo[2.2.2]oct-3-yl)-2-benzo[1,3]dioxol-5-yl-benzoxazole-4-carboxamideN-(1-Azabicyclo[2.2.2]oct-3-yl)-2-benzofuran-5-ylbenzoxazole-4-carboxamideN-(1-Azabicyclo[2.2.2]oct-3-yl)-2-(2,3-dihydrobenzofuran-5-yl)benzoxazole-4-carboxamideN-(9-Methyl-9-azabicyclo[3.3.1]non-3-yl)-2-(2,4-dimethoxyphenyl)benzoxazole-4-carboxamide(S)-N-(1-Azabicyclo[2.2.2]oct-3-yl)-2-(2,4-dimethoxyphenyl)benzoxazole-4-carboxamideN-(9-Methyl-9-azabicyclo[3.3.1]non-3-yl)-2-(2,4-dichlorophenyl)benzoxazole-4-carboxamide(S)-N-(1-Azabicyclo[2.2.2]oct-3-yl)-2-(2,4-dichlorophenyl)benzoxazole-4-carboxamide(S)-N-(1-Azabicyclo[2.2.2]oct-3-yl)-2-(4-chloro-2-methoxyphenyl)benzoxazole-4-carboxamideN-(9-Methyl-9-azabicyclo[3.3.1]non-3-yl)-2-(4-chloro-2-methoxyphenyl)benzoxazole-4-carboxamide(S)-N-(1-Azabicyclo[2.2.2]oct-3-yl)-2-(4-methoxy-2-methylphenyl)benzoxazole-4-carboxamideN-(9-Methyl-9-azabicyclo[3.3.1]non-3-yl)-2-(4-methoxy-2-methylphenyl)benzoxazole-4-carboxamide(S)-N-(1-Azabicyclo[2.2.2]oct-3-yl)-2-(4-chloro-2-methylphenyl)benzoxazole-4-carboxamideN-(9-Methyl-9-azabicyclo[3.3.1]non-3-yl)-2-(4-chloro-2-methylphenyl)benzoxazole-4-carboxamideN-(9-Methyl-9-azabicyclo[3.3.1]non-3-yl-2-(2,6-dimethylphenyl)benzoxazole-4-carboxamide(S)-N-(1-Azabicyclo[2.2.2]oct-3-yl)-2-(2,6-dichlorophenyl)benzoxazole-4-carboxamideN-(9-Methyl-9-azabicyclo[3.3.1]non-3-yl)-2-(2,6-dichlorophenyl)benzoxazole-4-carboxamideN-(1-Azabicyclo[2.2.2]oct-3-yl)-6-chloro-2-p-tolylbenzoxazole-4-carboxamideN-(9-Methyl-9-azabicyclo[3.3.1]non-3-yl)-6-chloro-2-p-tolylbenzoxazole-4-carboxamideN-(1-Azabicyclo[2.2.2]oct-3-yl)-6-chloro-2-(4-methoxyphenyl)benzoxazole-4-carboxamideN-(9-Methyl-9-azabicyclo[3.3.1]non-3-yl)-6-chloro-2-(4-methoxyphenyl)benzoxazole-4-carboxamideN-(1-Azabicyclo[2.2.2]oct-3-yl)-6-bromo-2-phenylbenzoxazole-4-carboxamideN-(9-Methyl-9-azabicyclo[3.3.1]non-3-yl)-6-bromo-2-phenylbenzoxazole-4-carboxamideN-(1-Azabicyclo[2.2.2]oct-3-yl)-6-bromo-2-p-tolylbenzoxazole-4-carboxamideN-(9-Methyl-9-azabicyclo[3.3.1]non-3-yl)-6-bromo-2-p-tolylbenzoxazole-4-carboxamideN-(1-Azabicyclo[2.2.2]oct-3-yl)-6-bromo-2-(4-methoxyphenyl)benzoxazole-4-carboxamideN-(9-Methyl-9-azabicyclo[3.3.1]non-3-yl)-6-bromo-2-(4-methoxyphenyl)benzoxazole-4-carboxamideN-(9-Methyl-9-azabicyclo[3.3.1]non-3-yl)-6-amino-2-phenylbenzoxazole-4-carboxamideDihydrochlorideN-(1-Azabicyclo[2.2.2]oct-3-yl)-5-bromo-2-phenylbenzoxazole-4-carboxamideN-(9-Methyl-9-azabicyclo[3.3.1]non-3-yl)-5-bromo-2-phenylbenzoxazole-4-carboxamideN-(9-Methyl-9-azabicyclo[3.3.1]non-3-yl)-7-bromo-2-phenylbenzoxazole-4-carboxamideN-(1-Azabicyclo[2.2.2]oct-3-yl)-7-bromo-2-phenylbenzoxazole-4-carboxamideN-(1-Azabicyclo[2.2.2]oct-3-yl)-6-iodo-2-phenylbenzoxazole-4-carboxamideN-(9-Methyl-9-azabicyclo[3.3.1]non-3-yl)-6-iodo-2-phenylbenzoxazole-4-carboxamideN-(1-Azabicyclo[2.2.2]oct-3-yl)-6-morpholine-2-phenylbenzoxazole-4-carboxamideN-(1-Azabicyclo[2.2.2]oct-3-yl)-6-amino-2-phenylbenzoxazole-4-carboxamideN-(1-Azabicyclo[2.2.2]oct-3-yl)-6-acetylamino-2-phenylbenzoxazole-4-carboxamide(S)-N-(1-Azabicyclo[2.2.2]oct-3-yl)-6-methoxy-2-phenylbenzoxazole-4-carboxamideN-(9-Methyl-9-azabicyclo[3.3.1]non-3-yl)-6-methoxy-2-phenylbenzoxazole-4-carboxamide(S)-N-(1-Azabicyclo[2.2.2]oct-3-yl)-6-hydroxy-2-phenylbenzoxazole-4-carboxamide(S)-N-(1-Azabicyclo[2.2.2]oct-3-yl)-6-fluoro-2-phenylbenzoxazole-4-carboxamideN-(9-Methyl-9-azabicyclo[3.3.1]non-3-yl)-6-fluoro-2-phenyl)benzoxazole-4-carboxamide(S)-N-(1-Azabicyclo[2.2.2]oct-3-yl)-6-fluoro-2-(2-methoxyphenyl)benzoxazole-4-carboxamideHydrochlorideN-(9-Methyl-9-azabicyclo[3.3.1]non-3-yl)-6-fluoro-2-(2-methoxyphenyl)benzoxazole-4-carboxamideHydrochlorideN-(9-Methyl-9-azabicyclo[3.3.1]non-3-yl)-2-pyridin-4-ylbenzoxazole-4-carboxamide(S)-N-(1-Azabicyclo[2.2.2]oct-3-yl)-2-furan-2-ylbenzoxazole-4-carboxamideN-(9-Methyl-9-azabicyclo[3.3.1]non-3-yl)-2-furan-2-ylbenzoxazole-4-carboxamide(S)-N-(1-Azabicyclo[2.2.2]oct-3-yl)-2-thiophen-2-ylbenzoxazole-4-carboxamideN-(9-Methyl-9-azabicyclo[3.3.1]non-3-yl)-2-thiophen-2-ylbenzoxazole-4-carboxamideN-(9-Methyl-9-azabicyclo[3.3.1]non-3-yl)-6-chloro-2-thiophen-2-ylbenzoxazole-4-carboxamide(S)-N-(1-Azabicyclo[2.2.2]oct-3-yl)-6-chloro-2-thiophen-2-ylbenzoxazole-4-carboxamide(S)-N-(1-Azabicyclo[2.2.2]oct-3-yl)-2-thiophen-3-ylbenzoxazole-4-carboxamideN-(9-Methyl-9-azabicyclo[3.3.1]non-3-yl)-2-thiophen-3-ylbenzoxazole-4-carboxamideN-(9-Methyl-3-oxa-9-azabicyclo[3.3.1]non-7-yl)-6-chloro-2-thiophen-3-ylbenzoxazole-4-carboxamideN-(9-Methyl-9-azabicyclo[3.3.1]non-3-yl)-6-chloro-2-thiophen-3-ylbenzoxazole-4-carboxamide(S)-N-(1-Azabicyclo[2.2.2]oct-3-yl)-6-chloro-2-thiophen-3-ylbenzoxazole-4-carboxamide(S)-N-(1-Azabicyclo[2.2.2]oct-3-yl)-2-benzo[b]thiophen-2-ylbenzoxazole-4-carboxamideN-(9-Methyl-9-azabicyclo[3.3.1]non-3-yl)-2-benzo[b]thiophen-2-ylbenzoxazole-4-carboxamide(S)-N-(1-Azabicyclo[2.2.2]oct-3-yl)-2-benzofuran-2-ylbenzoxazole-4-carboxamideN-(9-Methyl-9-azabicyclo[3.3.1]non-3-yl)-2-benzofuran-2-ylbenzoxazole-4-carboxamide(S)-N-(1-Azabicyclo[2.2.2]oct-3-yl)-2-(3-methylthiophen-2-yl)benzoxazole-4-carboxamideN-(9-Methyl-9-azabicyclo[3.3.1]non-3-yl)-2-(3-methylthiophen-2-yl)benzoxazole-4-carboxamideN-(9-Methyl-9-azabicyclo[3.3.1]non-3-yl)-6-chloro-2-(3-methylthiophen-2-yl)benzoxazole-4-carboxamide(S)-N-(1-Azabicyclo[2.2.2]oct-3-yl)-2-(3-chlorothiophen-2-yl)benzoxazole-4-carboxamideN-(9-Methyl-9-azabicyclo[3.3.1]non-3-yl)-2-(3-chlorothiophen-2-yl)benzoxazole-4-carboxamide(S)-N-(1-Azabicyclo[2.2.2]oct-3-yl)-2-(3-bromothiophen-2-yl)benzoxazole-4-carboxamideN-(9-Methyl-9-azabicyclo[3.3.1]non-3-yl)-2-(3-bromothiophen-2-yl)benzoxazole-4-carboxamide(S)-N-(1-Azabicyclo[2.2.2]oct-3-yl)-6-chloro-2-(3-chlorothiophen-2-yl)benzoxazole-4-carboxamideN-(9-Methyl-9-azabicyclo[3.3.1]non-3-yl)-6-chloro-2-(3-chlorothiophen-2-yl)benzoxazole-4-carboxamide(S)-N-(1-Azabicyclo[2.2.2]oct-3-yl)-2-(5-methylthiophen-2-yl)benzoxazole-4-carboxamide(S)-N-(1-Azabicyclo[2.2.2]oct-3-yl)-2-(5-chloro-thiophen-2-yl)benzoxazole-4-carboxamideN-(9-Methyl-9-azabicyclo[3.3.1]non-3-yl)-2-(5-chlorothiophene-2-yl)benzoxazole-4-carboxamide(S)-N-(1-Azabicyclo[2.2.2]oct-3-yl)-2-(5-bromothiophene-2-yl)benzoxazole-4-carboxamideN-(9-Methyl-9-azabicyclo[3.3.1]non-3-yl)-2-(5-bromothiophene-2-yl)benzoxazole-4-carboxamide(S)-N-(1-Azabicyclo[2.2.2]oct-3-yl)-6-chloro-2-(5-methylthiophen-2-yl)benzoxazole-4-carboxamideN-(9-Methyl-9-azabicyclo[3.3.1]non-3-yl)-6-chloro-2-(5-methylthiophen-2-yl)benzoxazole-4-carboxamide(S)-N-(1-Azabicyclo[2.2.2]oct-3-yl)-2-(5,6-dihydro-4H-cyclopenta[b]thiophen-2-yl)benzoxazole-4-carboxamideN-(9-Methyl-9-azabicyclo[3.3.1]non-3-yl)-2-(5,6-dihydro-4H-cyclopenta[b]thiophen-2-yl)benzoxazole-4-carboxamide(S)-N-(1-Azabicyclo[2.2.2]oct-3-yl)-2-(3,5-dimethylisoxazole-4-yl)benzoxazole-4-carboxamideN-(9-Methyl-9-azabicyclo[3.3.1]non-3-yl)-2-(3,5-dimethylisoxazole-4-yl)benzoxazole-4-carboxamide(S)-N-(1-Azabicyclo[2.2.2]oct-3-yl)-2-(4-methylthiazol-5-yl)benzoxazole-4-carboxamideHydrochlorideN-(9-Methyl-9-azabicyclo[3.3.1]non-3-yl)-2-(4-methylthiazol-5-yl)benzoxazole-4-carboxamideHydrochloride(S)-N-(1-Azabicyclo[2.2.2]oct-3-yl)-2-(thiazole-4-yl)benzoxazole-4-carboxamideHydrochlorideN-(9-Methyl-9-azabicyclo[3.3.1]non-3-yl)-2-(thiazol-4-yl)benzoxazole-4-carboxamideHydrochloride(S)-N-(1-Azabicyclo[2.2.2]oct-3-yl)-2-(2-oxo-1,2-dihydropyridin-3-yl)benzoxazole-4-carboxamideN-(9-Methyl-9-azabicyclo[3.3.1]non-3-yl)-2-(2-oxo-1,2-dihydropyridin-3-yl)benzoxazole-4-carboxamideN-(9-Methyl-9-azabicyclo[3.3.1]non-3-yl)-2-(2-morpholinophenyl)benzoxazole-4-carboxamideMaleateN-(9-Methyl-9-azabicyclo[3.3.1]non-3-yl)-2-[2-(4-methylpiperazin-1-yl)phenyl]benzoxazole-4-carboxamideMaleateN-(9-Methyl-9-azabicyclo[3.3.1]non-3-yl)-2-(2-isopropylphenyl)benzoxazole-4-carboxamideHydrochloride and(S)-N-(1-Azabicyclo[2.2.2]oct-3-yl)-2-(2-isopropylphenyl)benzoxazole-4-carboxamideHydrochloride.
 17. A pharmaceutical composition comprising apharmaceutically acceptable carrier and a therapeutically effectiveamount of a compound according to claim 1 or
 3. 18. A pharmaceuticalcomposition according to claim 17 additionally comprising a secondantiemetic agent.
 19. A pharmaceutical composition according to claim 18wherein said second antiemetic agent is a neurokinin antagonist.
 20. Amethod of treating a disorder which is dependent upon modulation of theserotonin type 3 receptor, which comprises administering to a patient inneed of such treatment a therapeutically effective amount of a compoundaccording to claim 1 or
 3. 21. A method according to claim 20 whereinsaid disorder is irritable bowel syndrome.
 22. A method according toclaim 20 for treating emesis. 23-34. (canceled)